Benzimidazole derivatives, preparation and therapeutic use thereof

ABSTRACT

The invention relates to benzimidazole derivatives of general formula  
                 
in which X represents a nitrogen atom or a carbon atom; and when X represents a nitrogen atom: R3 represents a hydrogen atom or a C1-C4 alkyl group, or does not exist, to give the compounds of formula (I) comprising a secondary or tertiary amine; 
         R4 represents a hydrogen atom or a C1-C6 alkyl, C3-C7 cycloalkyl, optionally substituted C3-C7 heterocycloalkyl, —(CH 2 ) p -heteroaryl, heteroaryl-carbonyl, phenylcarbonyl, (C1-C6)alkylcarbonyl, —(CH 2 ) p COOR, optionally substituted phenylsulphonyl or optionally substituted —(CH 2 ) p -phenyl group, and, when X represents a carbon atom:    R3 represents a hydrogen atom or a group —NR5R6, —N(R5) 3   + , —NHCOR7, —CONHR5, —COR7, —NHCONH 2 , —OH or —CH 2 OH,    R4 represents a hydrogen atom or an optionally substituted —(CH 2 ) p -phenyl, —(CH 2 ) p -heteroaryl or —(CH 2 ) t NR7R8 group. Preparation process and therapeutic application.

The present invention relates to benzimidazole derivatives, to theirpreparation and to their therapeutic application.

The present invention relates to compounds corresponding to formula (I):

-   -   in which:    -   R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogen        atom, a nitro group or a C1-C4 alkoxy group,    -   R2 and R240 represent, independently of each other, a hydrogen        atom or a C1-C4 alkyl group,    -   X represents a nitrogen atom or a carbon atom,    -   n is equal to 1 or 2,    -   m is equal to 1 or 2,    -   and, when X represents a nitrogen atom:    -   R3 represents a hydrogen atom or a C1-C4 alkyl group, to give        compounds of formula (I) comprising a quaternary ammonium, or        alternatively does not exist, to give compounds of formula (I)        comprising a secondary or tertiary amine,    -   R4 represents    -   a hydrogen atom,    -   a C1-C6 alkyl group,    -   a C3-C7 cycloalkyl group,    -   a C3-C7 heterocycloalkyl group optionally substituted with a        C1-C4 alkyl group or a group —COOR, in which R represents a        C1-C6 alkyl group,    -   a group —(CH₂)_(p)-heteroaryl, in which p may range from 0 to 4        and in which the heteroaryl group is chosen from pyridyl,        aminopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl        and thienyl groups, the said heteroaryl group optionally being        substituted with a C1-C4 alkyl group,    -   a heteroarylcarbonyl group, the heteroaryl group being chosen        from furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and        imidazolyl groups,    -   a phenylcarbonyl group, the phenyl group optionally being        substituted with a halogen atom,    -   a (C1-C6)alkylcarbonyl group,    -   a group —(CH₂)_(p)COOR in which p may range from 0 to 4 and in        which R represents a C1-C6 alkyl group,    -   a phenylsulphonyl group optionally substituted on the phenyl        nucleus with a halogen atom, a trifluoromethyl group, a C1-C4        alkyl group, a nitro group or a C1-C4 alkoxy group, or        alternatively    -   a —(CH₂)_(p)-phenyl group, in which p may range from 0 to 4 and        in which the phenyl group is optionally substituted, in the        ortho and/or meta and/or para position, with one to three groups        chosen, independently of each other, from: a C1-C4 alkyl group,        a nitro group, an amino group, a hydroxyl group, a halogen atom,        a trifluoromethyl group, a C1-C4 alkoxy group, a        (C1-C4)alkoxyphenyl group, a C1-C4 alkylamino group, a C1-C4        dialkylamino group, an —NHCHO group or a group —NHCOR′, in which        R′ represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this        C1-C4 alkyl group optionally being substituted with a        dimethylamino group,    -   and, when X represents a carbon atom:    -   R3 represents a hydrogen atom, a group —NR5R6, a group —N(R5)₃        ⁺, a group —NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH₂        group, an —OH group or a —CH₂OH group,    -   R4 represents    -   a hydrogen atom,    -   a —(CH₂)_(p)-phenyl group, in which p may range from 0 to 4 and        in which the phenyl group is optionally substituted with one to        three groups chosen, independently of each other, from: a C1-C4        alkyl group, a nitro group, an amino group, a halogen atom, a        trifluoromethyl group or a C1-C4 alkoxy group,    -   a —(CH₂)_(p)-heteroaryl group, in which p may range from 0 to 4        and in which the heteroaryl group is chosen from an imidazolyl        group, optionally substituted with a C1-C4 alkyl group, a        pyridyl group, an aminopyridyl group, a pyrimidinyl group, a        pyrazinyl group or a pyridazinyl group, or alternatively    -   a group —(CH₂)_(t)NR7R8, in which t is equal to 0 or 1,    -   with the proviso that when R4 represents a group —NR7R8, R3 is        other than the groups —NR5R6, —NHCOR7, —NHCONH₂ and —OH,    -   R5 and R6 represent, independently of each other, a hydrogen        atom or a C1-C4 alkyl group,    -   R7 and R8 represent, independently of each other, a C1-C4 alkyl        or C1-C4 alkoxy group or together form a saturated 5- to        7-membered ring optionally comprising an additional nitrogen        atom, to form, for example, a 1-piperidyl group, a        1-pyrrolidinyl group or a 1-piperazinyl group, this ring        optionally being substituted, on a carbon atom or on a nitrogen        atom, including the nitrogen atom to which the groups R7 and R8        are attached to form a quaternary ammonium, with a C1-C4 alkyl        group or a group —COOR″, in which R″ represents a phenyl or        (C1-C4)alkylphenyl group,    -   with the exclusion of the two compounds for which        R1=R2=R2′=R3=H, X=C, n=m=1 and R4 represents either a        4-imidazolyl group or a 5-methyl-4-imidazolyl group.

These two compounds are disclosed in patent application EP 646 583, ascompounds 16 and 17 in the table, as 5-HT₃ and 5-HT₄ type serotoninergicreceptor ligands.

The compounds of formula (I) may comprise one or more asymmetric carbonatoms. They may thus exist in the form of enantiomers ordiastereoisomers. These enantiomers and diastereoisomers, and also themixtures thereof, including racemic mixtures, form part of theinvention.

The compounds of the invention may exist in the form of bases or ofaddition salts with pharmaceutically acceptable acids. Such additionsalts also form part of the invention.

In the context of the present invention, the term:

-   -   “a (Cq-Cr)alkyl group” means a linear or branched saturated        aliphatic group comprising from q to r carbon atoms, q and r        being integers; mention may be made in particular of methyl,        ethyl, propyl, isopropyl, n-propyl, butyl, isobutyl, tert-butyl,        n-butyl, pentyl, etc. groups;    -   “a halogen atom” means a fluorine, a chlorine, a bromine or an        iodine;    -   “a C3-C7 cycloalkyl group” means a cyclic alkyl group containing        from 3 to 7 carbon atoms; mention may be made in particular of        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl        groups;    -   “a C3-C7 heterocycloalkyl group” means a cyclic alkyl group        containing from 3 to 7 carbon atoms and also one or more hetero        atoms, for example a nitrogen atom; mention may be made in        particular of piperidyl groups;    -   “a (C1-C4)alkoxyphenyl group” means a group of formula        —O—(CH₂)_(x)-phenyl, in which x may range from 1 to 4.

Among the compounds of formula (I) which are the subjects of the presentinvention, mention may be made of the preferred compounds for which:

-   -   R1 represents a hydrogen atom, a C1-C4 alkyl group or a C1-C4        alkoxy group,    -   R2 represents a hydrogen atom or a C1-C4 alkyl group,    -   R2′ represents a hydrogen atom,    -   X represents a nitrogen atom,    -   n is equal to 1 or 2,    -   m is equal to 1 or 2,    -   R3 represents a hydrogen atom, to give compounds of formula (I)        comprising a quaternary ammonium, or alternatively does not        exist, to give compounds of formula (I) comprising a secondary        or tertiary amine,    -   R4 represents    -   a hydrogen atom,    -   a C1-C6 alkyl group,    -   a C3-C7 cycloalkyl group,    -   a pyridyl, pyrimidinyl or pyrazinyl group, optionally        substituted with a C1-C4 alkyl group,    -   a heteroarylcarbonyl group, the heteroaryl group being chosen        from a furyl group and a pyridyl group,    -   a phenylcarbonyl group, the phenyl group optionally being        substituted with a halogen atom,    -   a (C1-C6)alkylcarbonyl group,    -   a group —(CH₂)_(p)COOR in which p can range from 0 to 4 and in        which R represents a C1-C6 alkyl group,    -   a phenylsulphonyl group,    -   a phenyl group substituted with one to three groups chosen,        independently of each other, from: a C1-C4 alkyl group, a nitro        group, an amino group, a hydroxyl group, a halogen atom, a        trifluoromethyl group, a C1-C4 alkoxy group, a        (C1-C4)alkoxyphenyl group, a (C1-C4)dialkylamino group, an        —NHCHO group or a group —NHCOR′, in which R′ represents a C1-C4        alkoxy group or a C1-C4 alkyl group, this C1-C4 alkyl group        optionally being substituted with a dimethylamino group,    -   a —(CH₂)_(p)-phenyl group, in which p can range from 0 to 4,    -   a —(CH₂)_(p)-pyridyl group, in which p can range from 0 to 4,    -   a —(CH₂)_(p)-thienyl group, in which p can range from 0 to 4,    -   a (C3-C7)heterocycloalkyl group optionally substituted with a        C1-C4 alkyl group or a group —COOR, in which R represents a        C1-C6 alkyl group,    -   or alternatively the preferred compounds for which:    -   R1 represents a hydrogen atom,    -   R2 and R2′ represent, independently of each other, a hydrogen        atom or a C1-C4 alkyl group,    -   X represents a carbon atom,    -   n is equal to 1 or 2,    -   m is equal to 1,    -   R3 represents a hydrogen atom, a group —NR5R6, a group —N(R5)₃        ⁺, a group —NHCOR7, a group —CONHR5, an —NHCONH₂ group, an —OH        group or a —CH₂OH group,    -   R4 represents    -   a hydrogen atom,    -   a benzyl group (namely a —(CH₂)_(p)-phenyl group in which p is        equal to 1),    -   a phenyl group optionally substituted with one to three groups        chosen, independently of each other, from: a C1-C4 alkyl group,        a nitro group, an amino group, a halogen atom, a trifluoromethyl        group or a C1-C4 alkoxy group,    -   a heteroaryl group chosen from an imidazolyl group, optionally        substituted with a C1-C4 alkyl group, or a pyridyl group,    -   a group —NR7R8,    -   with the proviso that when R4 represents a group —NR7R8, R3 is        other than the groups —NR5R6, —NHCOR7, —NHCONH₂ and —OH,    -   R5 and R6 represent, independently of each other, a hydrogen        atom or a C1-C4 alkyl group,    -   R7 and R8 represent, independently of each other, a C1-C4 alkyl        or C1-C4 alkoxy group, or together form a saturated 5- to        7-membered ring optionally comprising an additional nitrogen        atom, this ring optionally being substituted, on a carbon atom        or a nitrogen atom, including the nitrogen atom to which the        groups R7 and R8 are attached to form a quaternary ammonium,        with a C1-C4 alkyl group or a group —COOR″, in which R″        represents a phenyl or (C1-C4)alkylphenyl group,    -   with the exclusion of the two compounds for which        R1=R2=R2′=R3=H, X=C, n=m=1 and R4 represents either a        4-imidazolyl group or a 5-methyl-4-imidazolyl group.

Among the latter preferred compounds, ones most particularly preferredare the compounds of formula (I) for which:

-   -   R1 represents a hydrogen atom, a methyl group or a methoxy        group,    -   R2 represents a hydrogen atom or a methyl group,    -   R2′ represents a hydrogen atom,    -   X represents a nitrogen atom,    -   n is equal to 1 or 2,    -   m is equal to 1 or 2,    -   R3 represents a hydrogen atom, to give compounds of formula (I)        comprising a quaternary ammonium, or alternatively does not        exist, to give compounds of formula (I) comprising a secondary        or tertiary amine,    -   R4 represents    -   a hydrogen atom,    -   a C1-C4 alkyl group,    -   a C6-C7 cycloalkyl group,    -   a pyridyl, pyrimidinyl or pyrazinyl group, optionally        substituted with a C1-C4 alkyl group,    -   a heteroarylcarbonyl group, the heteroaryl group being chosen        from a furyl group and a pyridyl group,    -   a phenylcarbonyl group, the phenyl group optionally being        substituted with a halogen atom,    -   a (C3-C5)alkylcarbonyl group,    -   a group —(CH₂)_(p)COOR in which p is equal to 0 or 1 and in        which R represents a C1-C4 alkyl group,    -   a phenylsulphonyl group,    -   a phenyl group substituted with one to three groups chosen,        independently of each other, from: a methyl group, a nitro        group, an amino group, a hydroxyl group, a halogen atom, a        trifluoromethyl group, a methoxy group, a (C1-C4)alkoxyphenyl        group, a dimethylamino group, an —NHCHO group or a group        —NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4        alkyl group, this C1-C4 alkyl group optionally being substituted        with a dimethylamino group,    -   a —(CH₂)_(p)-phenyl group, in which p is equal to 1, 2, 3 or 4,    -   a —(CH₂)_(p)-pyridyl group, in which p can range from 1 to 3,    -   a —(CH₂)_(p)-thienyl group, in which p is equal to 2,    -   a C6-C7 heterocycloalkyl group optionally substituted with a        methyl group or a group —COOR, in which R represents a C1-C4        alkyl group,    -   or alternatively, the compounds that are most particularly        preferred are those of formula (I) for which:    -   R1 represents a hydrogen atom,    -   R2 and R2′ represent, independently of each other, a hydrogen        atom or a methyl group,    -   X represents a carbon atom,    -   n is equal to 1 or 2,    -   m is equal to 1,    -   R3 represents a hydrogen atom, a group —NR5R6, an —N(CH₃)₃ ⁺        group, a group —NHCOR7, a group —CONHR5, an —NHCONH₂ group, an        —OH group or a —CH₂OH group,    -   R4 represents    -   a hydrogen atom,    -   a benzyl group,    -   a phenyl group optionally substituted with one to three groups        chosen, independently of each other, from a halogen atom and a        trifluoromethyl group,    -   a heteroaryl group chosen from an imidazolyl group, optionally        substituted with a methyl group, or a pyridyl group,    -   a group —NR7R8,    -   with the proviso that when R4 represents a group —NR7R8, R3 is        other than the groups —NR5R6, —NHCOR7, —NHCONH₂ and —OH,    -   R5 and R6 represent, independently of each other, a hydrogen        atom or a C1-C4 alkyl group,    -   R7 and R8 represent, independently of each other, a C1-C4 alkyl        group or together form a saturated 5- to 7-membered ring        optionally comprising an additional nitrogen atom, this ring        optionally being substituted, on a carbon atom or on a nitrogen        atom, including the nitrogen atom to which the groups R7 and R8        are attached to form a quaternary ammonium, with a methyl group        or a group —COOR″, in which R″ represents a (C1-C4)alkylphenyl        group,    -   with the exclusion of the two compounds for which        R1=R2=R2′=R3=H, X=C, n=m=1 and R4 represents either a        4-imidazolyl group or a 5-methyl-4-imidazolyl group.

In the text hereinbelow, the term “leaving group” means a group whichmay be readily cleaved from a molecule by heterolytic cleavage of abond, with departure of an electron pair. This group may thus be readilyreplaced with another group during, for example, a substitutionreaction. Such leaving groups are, for example, halogens or an activatedhydroxyl group such as a mesyl, tosyl, triflate, acetyl, etc. Examplesof leaving groups and references for preparing them are given in“Advances in Organic Chemistry”, J. March 3rd Edition, WileyInterscience pp. 310-316.

To prepare the compounds of formula (I) in accordance with theinvention, the process is performed according to the synthetic scheme 1below. According to this process, a derivative of formula (II), in whichR1, R2, R2′ and n are as defined above and A represents a leaving group,preferably a halogen, are reacted in the presence of an amine of formula(III), in which X, R3, R4 and m are as defined above, in a solvent whichmay be an alcohol, such as isoamyl alcohol, an ether such astetrahydrofuran or TGME (triethylene glycol monomethyl ether) or ahydrocarbon such as toluene, at a temperature of between roomtemperature and the boiling point of the solvent, to give the compoundof formula (I). The reaction may be carried out in the presence of abase such as 2,6-dimethyllutidine or sodium tert-butoxide, in thepresence of alkali metal halides such as potassium fluoride or in thepresence of palladium-based or nickel-based catalysts, as described, forexample, in patent application EP 646 583 or in J. Med. Chem. (1986) 291178-1183, Tetrahedron Letters (1997) 32 5607-5610, Tetrahedron Letters(1999) 55 12829-12842 and Tetrahedron Letters (1999) 40 6875-6879.

When the compound of formula (I) comprises a free primary or secondaryamine function, it may also be obtained by reacting a derivative offormula (II) with an amine of formula (III) in which the said aminefunction is protected with a conventional amine-protecting group such asa tert-butyl carbamate (BOC). The compound of formula (I) containing aprotected amine function, thus obtained, is then treated according toone of the known methods to give the desired compound (I) containing afree amine function. Examples of amine-protecting groups and ofdeprotection methods are given in particular in T. W. Greene, P. G. M.Wuts, “Protective Groups in Organic Synthesis”, J. Wiley, Ed., 1991.

The compounds of formula (II) may be prepared according to Scheme 2below, according to operating conditions that are known to those skilledin the art, in particular by reacting a compound of formula (IV), inwhich R1, R2, n and R2′ are as defined above, with a halogenating agentsuch as phosphoryl chloride.

The compounds of formula (IV) may be prepared according to a processdescribed in synthetic scheme 2 above. According to one variant of thisprocess, a diamine of formula (V), in which R1, R2, R2′ and n are asdefined above, is coupled with a phosgene derivative such ascarbonyldiimidazole (CDI). According to another variant, a derivative offormula (VI), in which R1 is as defined above, is alkylated with analkylating agent of formula (VIII, R═C1-C4 alkyl) in which R2 is asdefined above, to give the products of formula (VII) in which n=1 andR2′=H, or with an agent of formula (IX, R=C1-C4 alkyl) and Y is aleaving group, in which R2 and R2′ are as defined above, to give theproducts of formula (VII) in which n=2. The compounds (VII) thusobtained are then converted into carboxylic acids (VII, R═H) or intoacid derivatives such as acid chlorides (VII, R═Cl) and then cyclizedunder operating conditions known to those skilled in the art, to givethe intermediates of formula (II) directly. An approach similar to thissecond variant is described in particular in patent application JP55111406 or in Tetrahedron Letters (1995) 36 1387-1390.

Alternatively, the compounds of formula (II) in which R2 and R2′ do notrepresent hydrogen atoms may be prepared from the correspondingcompounds (II) in which R2′ represents a hydrogen atom, by alkylationwith a reagent of the type R2′Z in which Z represents a leaving group,preferably iodine. This reaction may be carried out in a solvent such asdimethylformamide, ether or tetrahydrofuran in the presence of a base,according to methods known to those skilled in the art.

The compounds of formulae (III), (V), (VI), (VIII) and (IX) arecommercially available or may be prepared according to operatingconditions that are known to those skilled in the art.

A subject of the present invention is also the novel syntheticintermediates of formula (II).

The examples which follow illustrate the present invention. The numbersfor the compounds given as examples refer to those in the table givenlater, which illustrates the chemical structures of a number ofcompounds according to the invention.

EXAMPLE 1 Preparation of Intermediates of Formula (II)

1.1 Preparation of 2-chloro-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(A=Cl, R1=H, R2=R2′=H, n=1)

This compound is obtained from the compound4H-imidazo[4,5,1-ij]quinolin-2,6-(1H,5H)dione (IV), described inJapanese patent: JP 55111406. 10 g of compound (IV) are reacted atreflux with 38.6 mL of phosphorous oxychloride and 6.3 g of ammoniumchloride, for 1.5 hours, in a 250 mL three-necked flask fitted with areflux condenser. The reaction mixture is then cooled and poured ontoice, to which is added 20% aqueous ammonia solution with vigorousstirring, until a pH of 9 is obtained. The mixture is extracted withtwice 250 mL of ethyl acetate, dried over magnesium sulphate, filteredand evaporated. 9.81 g of a white solid are obtained and are usedwithout further purification in the following step. ¹H NMR (200 MHz, δppm) DMSO D6: 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (t, 1H), 4.5 (t, 2H), 3.0(t, 2H).

1.2 Preparation of1-chloro-8,9-dihydro-7H-2,9a-diazabenzo[cd]azulen-6-one (A=Cl, R1=H,R2=R2′=H, n=2)

1.2.1: Ethyl 3-(2-chlorobenzimidazol-1-yl)butyrate Sodium hydride as a60% dispersion in oil (2.88 g, 72 mmol) is introduced, under a nitrogenatmosphere, into a 1 L three-necked flask with a magnetic stirrer, anaddition funnel and a condenser, the sodium hydride is washed twice withpentane and a small amount of dimethylformamide is added, followed by asolution of ethyl 4-bromobutyrate (14.78 g, 72 mmol) in anhydrousdimethylformamide (200 mL). After stirring for one hour at roomtemperature, 2-chloro-1H-benzimidazole (10.0 g, 65.5 mmol) dissolved inanhydrous dimethylformamide (200 mL) is added to the mixture. Thereaction mixture is heated at 65° C. for 8 hours and is then kept atroom temperature overnight. After evaporation of the dimethylformamide,the residue is taken up in ethyl acetate and the organic phase is washedwith saturated sodium chloride, dried over magnesium sulphate, filteredand concentrated. A flash chromatography on silica gel (750 g) of thecrude product (22 g) with an elution gradient of from 10% to 30% ethylacetate in petroleum ether gives the title compound in the form of ayellow oil (16.58 g, 95%). ¹H NMR (300 MHz, δ ppm) CDCl₃: 1.25 (t, 3H),2.15 (quint., 2H), 2.40 (t, 2H), 4.15 (quartet, 2H), 4.25, (t, 2H),7.20-7.40 (m, 2H), 7.70 (dd, 1H).

1.2.2: Lithium 3-(2-chloro-1-benzimidazolyl)butoxide

The ethyl ester (16.58 g, 62.2 mmol) dissolved in tetrahydrofuran (180mL) is introduced into a 1 L one-necked round-bottomed flask withmagnetic stirring, followed by addition of aqueous lithium hydroxidesolution (1.49 g, 24 mmol, 100 mL of distilled water). The mixture isleft to react overnight at room temperature, the tetrahydrofuran andwater are evaporated off and the residue is then taken up in ethyl ether(2 L) and stirred for 2 hours. The white precipitate obtained isfiltered off, washed with ethyl ether and then dried thoroughly undervane-pump vacuum over phosphorous pentoxide to give the expectedcompound in the form of white crystals (14 g, 92%). The compound is usedwithout further purification for the following step. ¹H NMR (300 MHz, δppm) DMSO D6+ε D₂O: 1.85 (m, 2H), 1.95 (m, 2H), 4.20 (t, 2H), 7.25 (m,2H), 7.55 (d, 1H), 7.60 (d, 1H). LC-MS: MH⁺=239 (acid)

1.2.3: 1-Chloro-8,9-dihydro-7H-2,9a-diazabenzo[cd]-azulen-6-one

The lithium salt (11.95 g, 49.7 mmol) is introduced into a 2 Lthree-necked flask under an argon atmosphere, with magnetic stirring, acondenser and an addition funnel, followed by addition of1,2-dichloroethane freshly distilled over phosphorous pentoxide (1 L).Oxalyl chloride (8.55 mL, 102 mmol) is added quickly with stirring andthe reaction mixture is heated for 15 min at about 40° C. Aluminiumchloride (19.54 g, 154.5 mmol) is added to the intermediate acidchloride thus obtained and the mixture is refluxed for 3 hours. Theresulting mixture is cooled and then poured onto an ice/salt mixture andextracted with 1,2-dichloroethane, the organic phase is washed withsaturated sodium chloride solution, dried over magnesium sulphate andfiltered and the solvent is then evaporated off. A flash chromatographyof the crude product (10.6 g) on silica gel (800 g), eluting with 20%ethyl acetate in dichloromethane, gives the expected product in the formof white crystals (7.06 g, 65%). ¹H NMR (300 MHz, δ ppm) CDCl₃: 2.40(quint., 2H), 3.15 (t, 2H), 4.40, (t, 2H), 7.35 (t, 1H), 7.95 (d, 1H),8.05 (d, 1H). LC-MS: MH⁺=221.

1.3 Preparation of2-chloro-5-methyl-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one (A=Cl,R1=H, R2=CH₃, R2′=H, n=1)

1.3.1: Methyl 1-methyl-3-(2-chloro-1-benzimidazol-yl)propionate

2-Chloro-1H-benzimidazole (15.25 g, 100 mmol) dissolved in chloroform(100 mL) is introduced into a 1 L three-necked flask under a nitrogenatmosphere, with magnetic stirring, an addition funnel and a condenser.Triton B (47 mL, 110 mmol) and methyl methacrylate (107 mL, 1 mol) arethen added. The reaction mixture is refluxed for 2 hours, allowed tocool and the chloroform is then evaporated off. The residue is taken upin ethyl acetate and the organic phase is washed 3 times with water andonce with saturated sodium chloride solution. A flash chromatography ofthe crude product (16.0 g) on silica gel (1 kg) with an elution gradientof from 30% to 70% ethyl acetate in petroleum ether gives the expectedproduct in the form of white crystals (10.1 g, 40%). ¹H NMR (300 MHz, δppm) DMSO D6: 1.15, (d, 3H), 3.05 (m, 1H), 3.50 (s, 3H), 4.25 (dd, 1H),4.50 (dd, 1H), 7.25 (m, 2H), 7.60 (m, 2H).

1.3.2: Lithium 1-methyl-3-(2-chloro-1-benzimidazolyl)-propionate

This compound is obtained according to the method described in thepreparation in point 1.2, by treating methyl1-methyl-3-(2-chloro-1-benzimidazolyl)propionate with lithium hydroxide.¹H NMR (300 MHz, δ ppm) DMSO D6+ε D₂O: 1.35 (d, 3H), 2.60 (m, 1H), 4.10(dd, 1H), 4.40 (dd, 1H), 7.25 (m, 2H), 7.55 (d, 1H), 7.60 (d, 1H).LC-MS: MH⁺=239 (acid).

1.3.3: 2-Chloro-5-methyl-4,5-dihydroimidazo[4,5,1-ij]-quinolin-6-one

This compound is obtained from the lithium salt according to the methoddescribed in point 1.2 by treating it successively with oxalyl chlorideto give the intermediate acid chloride, and with aluminium chloride. ¹HNMR (300 MHz, δ ppm) DMSO D6: 1.40 (d, 3H), 3.20 (m, 1H), 4.10 (dd, 1H),4.65 (dd, 1H), 7.45 (t, 1H), 7.70 (d, 1H), 7.85 (d, 1H). LC-MS: MH⁺=221.

1.4 Preparation of2-chloro-4,5-dihydro-9-methylimidazo[4,5,1-ij]quinolin-6-one (A=Cl,R1=9-CH₃, R2=R2′=H, n=1)

1.4.1. 2-Hydroxy-4-methylbenzimidazole 2,3-Diaminotoluene (5 g, 41mmol), 1,1-carbonyldiimidazole (7.3 g, 45 mmol) and 50 mL of anhydrousDMF are successively introduced into a 250 mL two-necked flask under anargon atmosphere, with magnetic stirring. After heating the mixture at90-95° C. for 4 h, the solvent is distilled off under vacuum and theresidue obtained is taken up in water (250 mL) and extracted with ethylacetate (3×250 mL). The insoluble roduct formed during the extraction isrecovered (4.8 g) and the combined organic phases are washed again withsaturated NaCl solution, dried over MgSO₄, filtered and concentrated togive a further 1.2 g of desired product (6 g, quantitative). ¹H NMR (300MHz, δ ppm) DMSO D6: 2.27 (s, 3H), 6.72 (m, 2H), 6.82 (m, 1H).

1.4.2. 2-Chloro-4-methylbenzimidazole

2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL ofphosphoryl chloride are introduced into a 250 mL two-necked flask underan argon atmosphere, with magnetic stirring. The mixture is refluxed for20 hours and the phosphoryl chloride is evaporated off under vacuum. Thesolid obtained is taken up in water (250 mL), neutralized to pH=8 with28% aqueous ammonia and the aqueous phase is extracted with ethylacetate (3×250 mL). After the usual work-up, the title product isobtained in a yield of 93% (6.23 g). ¹H NMR (300 MHz, δ ppm) DMSO D6:2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).

1.4.3. Methyl 1-methyl-3-(2-chloro-4-methyl-1-benzimidazolyl)propionate

The title compound is prepared according to the procedure described inExample 1.3.1 (7.85 g, 94%). ¹H NMR (300 MHz, δ ppm) DMSO D6: 2.48 (s,3H), 2.86 (t, 2H), 3.56 (s, 3H), 4.49 (t, 2H), 7.06 (d, 1H), 7.19 (t,1H), 7.44 (d, 1H).

1.4.4. Lithium 1-methyl-3-(2-chloro-4-methyl-1-benzimidazolyl)propionate

The title compound is prepared according to the procedure described inExample 1.3.2. (6.94 g, 94%). ¹H NMR (300 MHz, δ ppm) DMSO D6: 2.3 (dd,2H), 2.48 (s, 3H), 4.32 (dd, 2H), 7.01 (d, 1H), 7.15 (t, 1H), 7.41 (d,1H) (acid).

1.4.5. 2-Chloro-4,5-dihydro-9-methylimidazo[4,5,1-ij]quinolin-6-one

The title compound is prepared according to the procedure described inExample 1.3.3. (4.72 g, 76%). ¹H NMR (300 MHz, δ ppm) DMSO D6: 2.58 (s,3H), 3.05 (t, 2H), 4.53 (t, 2H), 7.19, (d, 1H), 7.52 (d, 1H).

EXAMPLE 21-(6-Oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-4-piperidinopiperidine

(R1=R2=R2′=R3=H, R4=1-piperidyl, X=C, n=m=1) (compound 45)

400 mg of chloro derivative of formula (II) described in point 1.1, 5 mLof dimethylformamide, 70 mg of potassium fluoride, 0.2 mL of2,6-lutidine and 500 mg of 4-piperidinopiperidine are reacted togetherfor 2 hours at 140° C. After evaporation of the solvent, the residue ischromatographed on silica gel (eluent: dichloromethane+8% methanol). 375mg of product are obtained in the form of a whitish solid. ¹H NMR (200MHz, δ ppm) DMSO D6: 1.2-2.2 (m, 12H) 3.0 (M, 3H) 3.2-3.4 (m, 4H), 4.2(d, 2H), 4.65 (t, 2H), 7.4 (t, 1H), 7.6, (d, 1H), 7.8 (d, 1H).

EXAMPLE 31-Methyl-1-[1-(6-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-4-piperidinyl]piperidiniumchloride (R1=R2=R2′=R3=H, R4=N-methyl-1-piperidyl, X=C, n=1, m=1)(compound 48)

3.1: 4-(N-piperidino) Boc piperidine

3.98 g of 4-oxo-N-Boc piperidine, 1.7 g of piperidine and 7.1 g of Ti(IV) isopropoxide are mixed together in a three-necked round-bottomedflask under nitrogen, and the mixture is left stirring for one hour atroom temperature. 20 mL of absolute ethanol and 850 mg of NaBH₃CN arethen added. The resulting mixture is left to react for 17 hours at roomtemperature, 5 mL of water are added and the mixture is stirred for 5minutes and filtered through Whatman paper. The pink solution isevaporated, the residue is taken up in 100 mL of ethyl acetate and thesolution is dried over magnesium sulphate and evaporated. The residueobtained is chromatographed on 100 g of silica and eluted with acetone.2.2 g of oil, which crystallizes, are obtained, the NMR spectrum ofwhich corresponds to the expected structure, and the product is usedwithout further purification for the following step.

3.2: N-Boc-4-(N-methylpiperidinium)piperidine chloride

The compound obtained above (2.2 g) is stirred with 5 mL of CH₃I for 17hours in the absence of light, and then evaporated. 3.10 g of whitecrystals are obtained, which are used without further purification inthe following step.

3.3: 4-((N-methylpiperidinium)piperidine chloride

The crystals obtained above are suspended in 20 mL of dichloromethane towhich are added 5 mL of a saturated solution of hydrogen chloride inether. The gummy precipitate obtained is redissolved in 20 mL ofmethanol, evaporated to dryness and taken up in 5 mL of methanol. Thissolution is cooled to 0° C., 1.35 mL of sodium methoxide (at 30% inmethanol) are added and the mixture is stirred for 15 minutes, filteredand evaporated with a vacuum pump. The amine obtained is used withoutfurther purification for the following coupling.

3.4:1-Methyl-1-[l-(6-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-4-piperidyl]piperidiniumchloride

400 mg of 2-chloro-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one in 5mL of dimethylformamide, 70 mg of potassium fluoride, 0.2 mL of2,6-lutidine and 1.6 g of 4-(N-methylpiperidinium)piperidine chlorideare added to a three-necked flask under argon and left stirring for 5hours at 140° C. The mixture is evaporated on a vacuum pump and theresidue obtained is chromatographed with 70 g of Silica H (Merck)(eluent: dichloromethane with 10% methanol and 0.5% triethylamine). 50mg of pure product are obtained, the NMR spectrum of which correspondsto the desired structure.

EXAMPLE 42-[4-(4-Dimethylaminophenyl)piperazin-1-yl]4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(R1=R2=R2′=H, R3=-, R4=para-dimethylaminophenyl, X=N, n=m=1) (compound58)

4.1: 1-(tert-Butoxycarbonyl)-4-(4-dimethylamino-phenyl)piperazine

1-Bromo-4-N,N-dimethylaniline (0.85 g, 4.25 mmol), palladium acetate(0.039 g, 0.17 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP) (0.17 g, 0.25 mmol) and tBuOK (0.67 g, 5.95 mmol) aresuccessively introduced into a round-bottomed flask under a nitrogenatmosphere, fitted with a condenser, with magnetic stirring. The flaskis purged 3 times with nitrogen, toluene (25 mL) andN-tert-butoxycarbonylpiperazine (0.95 g, 5.1 mmol) are introduced andthe reaction mixture is refluxed for 20 hours. After cooling to roomtemperature, ethyl acetate is added and the organic phase is washedtwice with water. After drying the organic phase over sodium sulphate,filtering and concentrating, a residue (1.38 g) is obtained, which ischromatographed on silica gel with a gradient of dichloromethane/ethylacetate (9/1 to 1/1). The title compound is obtained in a yield of 50%(0.67 g). ¹H NMR (300 MHz, δ ppm) CDCl3: 1.47 (s, 9H), 2.99 (m, 4H),3.57 (m, 4H), 6.72 (d, 2H), 6.89 (d, 2H).

4.2: N-1-(4-Dimethylaminophenyl)piperazine

The product described in Example 1.1 (0.67 g, 2.2 mmol) is dissolved intrifluoroacetic acid (trifluoroacetic acid, 20 mL) and maintained undermagnetic stirring for 2.5 hours at room temperature. After evaporationof the trifluoroacetic acid, the residue is taken up in saturated sodiumcarbonate solution and the aqueous phase is extracted twice with ethylacetate. The combined organic phases are washed to neutrality withsaturated sodium chloride solution, dried over sodium sulphate andconcentrated. After chromatography of the residue on silica gel(95/5/0.1 dichloromethane/methanol/NH₄OH), the title product is obtainedin a yield of 69% (0.31 g, Rf: 0.1).

4.3: 2-[4-(4-Dimethylaminophenyl)piperazin-1-yl]4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one

The chloro intermediate described in point 1.1 (0.2 g, 0.969 mmol), 1 mLof triethylene glycol monomethyl ether (TGME), lutidine (0.125 mL, 1.07mmol), cesium fluoride (0.148 g, 0.969 mmol) and a solution of thederivative of Example 1.2 (0.219 g, 1.07 mmol) in TGME (1 mL) aresuccessively introduced into a round-bottomed flask fitted with acondenser, with magnetic stirring. The reaction mixture is heated at140° C. for 1.5 hours and allowed to cool, water is added and themixture is extracted twice with ethyl acetate. The organic phases arewashed twice with water, dried over sodium sulphate, filtered andconcentrated. The residue (0.38 g) is chromatographed on silica gel(ethyl acetate) and the oil obtained (0.246 g) is taken up in a smallamount of dichloromethane and crystallized by adding ether. The whitesolid, which corresponds to the expected compound (0.208 g, 57%) isfiltered off. LC-MS: MH+=376. ¹H NMR (360 MHz, δ ppm) DMSO D6: 2.79 (s,6H), 3.0 (t, 2H), 3.14 (m, 4H), 3.55 (m, 4H), 4.47 (t, 2H), 6.71 (d,2H), 6.91 (d, 2H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.60 (d, 1H).

EXAMPLE 52-[4-(4-tert-Butoxycarbonylaminophenyl)piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(R1=R2=R2′=H, R3=-, X=N, R4=4-tert-butyloxycarbonylaminophenyl, n=m=1)(compound 57)

5.1: 1-[2-(Trimethylsilyl)ethylcarbonyl]-4-(4-nitrophenyl)piperazine

A solution of 1-(4-nitrophenyl)piperazine (10 g, 48.31 mmol) and2-(trimethylsilyl)ethyl p-nitrophenyl carbonate (14.4 g, 50.73 mmol) intetrahydrofuran (220 mL) is refluxed for 3 hours with magnetic stirringand then stirred for 20 hours at room temperature. The reaction mixtureis concentrated, the residue is taken up in dichloromethane and theorganic phase is washed 4 times with 1N sodium hydroxide and twice withwater. The organic phase is then dried over sodium sulphate, filteredand concentrated; the oily residue obtained is used without furtherpurification in the following step (12 g, yield: 71%). ¹H NMR (300 MHz,δ ppm) CDCl3: 0.04 (s, 9H), 1.02 (m, 2H), 3.43 (m, 4H), 3.65 (m, 4H),4.22 (m, 2H), 6.82 (d, 2H), 8.13 (d, 2H).

5.2: 1-[2-(Trimethylsilyl)ethylcarbonyl]-4-(4-aminophenyl)piperazine

A mixture of the nitro derivative described above (12 g, 34.2 mmol) andof 4 to 5 spatulas of Raney nickel in 300 mL of ethanol is maintainedunder a hydrogen atmosphere, at atmospheric pressure, for 18 hours, withvigorous magnetic stirring. After filtration and concentration, theresidue obtained is used without further purification in the followingstep: the expected product, which is present at about 50% according tothe NMR and LC-MS, is difficult to purify. ¹H NMR (300 MHz, δ ppm)CDCl3: 0.04 (s, 9H), 1.03 (m, 2H), 2.96 (m, 4H), 3.59 (m, 4H), 4.18 (m,2H), aromatic protons not assignable, due to the presence of impurities.

5.3:1-[2-(Trimethylsilyl)ethylcarbonyl]-4-(4-tert-butoxycarbonylaminophenyl)piperazine

The crude reaction mixture from the above step (evaluated as 31 mmol)and di-tert-butyl dicarbonate (7.5 g, 34.1 mmol) in tetrahydrofuran (50mL) are successively added to a round-bottomed flask fitted with acondenser, and the mixture is refluxed for 44 hours. The tetrahydrofuranis evaporated off, the residue is taken up in a water/ethyl acetatemixture and the organic phase is washed twice with water. The organicphase is dried over sodium sulphate and concentrated, and the residue ischromatographed on silica gel (1/1 dichloro-methane/ethyl acetate). Theimpure product obtained is used without further purification for thefollowing step. LC-MS: MH+=422.

5.4: 1-(4-tert-Butoxycarbonylaminophenyl)piperazine

The intermediate described in the above point (3 g, considered as 7.12mmol) and tetrabutylammonium fluoride (3.37 g, 10.68 mmol) intetrahydrofuran (60 mL) are successively introduced into around-bottomed flask equipped with a condenser, with magnetic stirring.The reaction mixture is refluxed for 2 hours and concentrated, and theresidue is taken up in water and ethyl acetate. The organic phase iswashed twice with water and then with saturated sodium chloridesolution, dried over sodium sulphate and concentrated. The titlecompound (0.99 g, 50% over 3 steps) is obtained after chromatography onsilica gel (90/10/0.1 dichloromethane/methanol/NH₄OH). ¹H NMR (300 MHz,δ ppm) CDCl3: 1.50 (s, 9H), 3.04 (m, 8H), 6.60 (s, 1H), 6.87 (d, 2H),7.23 (d, 2H).

5.5:2-[4-(4-tert-Butoxycarbonylaminophenyl)piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one

The chloro intermediate described in point 1.1 (0.7 g, 3.39 mmol), TGME(7 mL), lutidine (0.43 mL, 3.73 mmol), cesium fluoride (0.514 g, 3.39mmol) and 1-(4-tert-butoxycarbonylaminophenyl)piperazine (1.03 g, 3.73mmol) are successively introduced into a round-bottomed flask fittedwith a condenser, with magnetic stirring. The reaction mixture is heatedat 140° C. for 2 hours and allowed to cool, water is added and themixture is extracted twice with ethyl acetate. The organic phases arewashed twice with water, dried over sodium sulphate, filtered andconcentrated. Chromatography of the residue on silica gel(dichloromethane/ethyl acetate gradient: 75/25 to 1/1) gives theexpected compound, which is then crystallized in a dichloromethane/ethermixture to give a white solid (1.1 g, 73%). LC-MS: MH+=448. ¹H NMR (500MHz, δ ppm) DMSO D6: 1.45 (s, 9H), 3.00 (t, 2H), 3.22 (m, 4H), 3.55 (m,4H), 4.47 (t, 2H), 6.91 (d, 2H), 7.15 (dd, 1H), 7.33 (m, 2H), 7.35 (d,1H), 7.61 (d, 1H).

EXAMPLE 62-[4-(4-Aminophenyl)piperazin-1-yl]4,5-dihydroimidazo[4,5,1-ij]quinolin-6-onedihydrochloride (R1=R2=R2′=H, R3=-, R4=para-aminophenyl, X=N, n=m=1)(compound 50)

A solution of hydrogen chloride gas in ethanol is added to the compoundof Example 5 (0.22 g, 0.497 mmol) and the reaction mixture is stirred atroom temperature for 2 hours. The resulting mixture is concentrated andthe expected compound is obtained, after trituration from ether, in theform of a white solid (0.155 g, 80%). ¹H NMR (500 MHz, δ ppm) DMSO D6:3.06 (t, 2H), 3.63 (m,4H), 3.84 (m, 4H), 4.65 (t, 2H), 7.10 (d, 2H),7.26 (d, 2H), 7.36 (dd, 1H), 7.54 (d, 1H), 7.71 (d, 1H), 10.06 (broadpeak, 2H).

EXAMPLE 72-[4-(4-Acetamidophenyl)piperazin-1-yl]4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(R1=R2=R2′=H, R3=-, R4=para-acetamidophenyl, X=N, n=m =1) (compound 60)

The compound of Example 6 (0.20 g, 0.48 mmol) and triethylamine (80 μL,0.572 mmol) are added to a solution of acetic acid (27 μL, 0.468 mmol)and carbonyldiimidazole (0.152 g, 0.936 mmol) in DMF (4 mL). Thereaction mixture is maintained under magnetic stirring at 70° C. for 20hours. After evaporation of the DMF under vacuum, the residue is takenup in water and triturated, and the solid obtained is filtered off.Washing the solid with a minimum amount of dichloromethane and then withether gives the expected compound (0.12 g, 64%). ¹H NMR (500 MHz, δ ppm)DMSO D6: 1.99 (s, 3H), 3.00 (t, 2H), 3.25 (m, 4H), 3.55 (m, 4H), 4.48(t, 2H), 6.94 (d, 2H), 7.15 (dd, 1H), 7.35 (d, 1H), 7.44 (d, 2H), 7.61(d, 1H), 9.70 (s, 1H).

EXAMPLE 82-(4-n-Propylpiperazin-1-yl)-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-onedihydrochloride (R1=R2=R2′=R4=H, X=N, R3=n-propyl, n=m=1) (compound 26)

The intermediate of formula (II) from point 1.1 (0.2 g, 0.969 mmol), 1mL of triethylene glycol monomethyl ether (TGME), lutidine (0.37 mL,3.30 mmol), cesium fluoride (0.148 g, 0.969 mmol) and a solution ofN-propylpiperazine dihydrobromide (0.296 g, 1.18 mmol) in TGME (1 mL)are successively introduced into a round-bottomed flask equipped with acondenser, with magnetic stirring. The reaction mixture is heated at140° C. for 2 hours 15 minutes and allowed to cool, saturated sodiumcarbonate solution and solid sodium chloride are added and the mixtureis extracted twice with ethyl acetate. The organic phases are washedtwice with saturated sodium chloride solution, dried over sodiumsulphate, filtered and concentrated. The residue obtained ischromatographed on silica gel (95/5/0.5 dichloromethane/methanol/NH₄OH)and the dihydrochloride salt of the oil obtained (0.203 g) issynthesized by dissolving it in a small amount of dichloromethane andadding a saturated solution of hydrogen chloride gas in anhydrous ether.The white solid, which corresponds to the expected product (0.23 g), isfiltered off. LC-MS: MH+=299. ¹H NMR (360 MHz, δ ppm) DMSO D6: 0.94 (t,3H), 1.78 (m, 2H), 3.08 (m, 4H), 3.28 (m, 2H), 3.62 (3, 2H), 3.88 (m,2H), 4.25 (m, 2H), 4.65 (t, 2H), 7.42 (t, 1H), 7.60 (d, 1H), 7.76 (d,1H), 11.66 (s, 1H).

EXAMPLE 92-(4-tert-Butyloxycarbonylpiperazin-1-yl)-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(R1=R2=R2′=H, R3=-, X=N, R4=tert-butyloxycarbonyl, n=m=1) (compound 12)

The intermediate described in point 1.1 (0.25 g, 1.2 mmol), TGME (1.5mL), lutidine (0.155 mL, 1.33 mmol), cesium fluoride (0.184 g, 1.21mmol) and a solution of tert-butyl-1-piperazine carboxylate (0.237 g,1.28 mmol) in TGME (1.5 mL) are successively introduced into around-bottomed flask equipped with a condenser, with magnetic stirring.The reaction mixture is heated at 120° C. for 3 hours and allowed tocool, water is added and this mixture is extracted twice with ethylacetate. The organic phases are washed twice with water, dried oversodium sulphate, filtered and concentrated. The residue obtained ischromatographed on silica gel (1/1 dichloromethane/ethyl acetate) togive the expected compound in the form of a white solid (0.315 g, 73%).LC-MS: MH+=357. ¹H NMR (500 MHz, δ ppm) DMSO D6: 1.51 (s, 9H), 3.07 (t,2H), 3.46 (m, 4H), 3.58 (m, 4H), 4.52 (t, 2H), 7.23 (t, 1H), 7.43 (d,1H), 25 7.68 (d, 1H).

EXAMPLE 10 2-(Piperazin-1-yl)-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-onedihydrochloride (R1=R2=R2′=R3=R4=H, X=N, n=m=1) (compound 13)

A saturated solution of hydrogen chloride gas in anhydrous ether isadded to a compound of Example 9 (0.1 g, 0.28 mmol) predissolved in aminimum amount of methanol, and the mixture is maintained under magneticstirring at room temperature overnight. This mixture is concentrated andthe residue is crystallized in a methanol/dichloromethane mixture. Theexpected compound is obtained in the form of a white solid (0.07 g).LC-MS: MH+=257. ¹H NMR (500 MHz, δ ppm) DMSO D6: 3.12 (t, 2H), 3.95 (m,4H), 3.94 (m, 4H), 4.66 (t, 2H), 7.43 (t, 1H), 7.61 (d, 1H), 7.80 (d,1H), 9.63 (s, 2H).

EXAMPLE 112-(4-Acetylpiperazin-1-yl)-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-onedihydrochloride (R1=R2=R2′=H, R3=-, R4=COCH₃, X=N, n=m=1) (compound 15)

The compound of Example 10 (0.085 g, 0.26 mmol) and triethylamine (75μL, 0.52 mmol) are added to a solution of acetic acid (20 μL, 0.349mmol), hydroxybenzotriazole (0.055 g, 0.349 mmol) and diisopropylazodicarboxylate (55 μL, 0.349 mmol) in ichloromethane (5 mL). Thereaction mixture is maintained under magnetic stirring at roomtemperature overnight and is diluted with ethyl acetate and 1Nhydrochloric acid solution. The crude product is obtained by the usualacid-base extraction and aqueous washes, followed by drying the organicphases over sodium sulphate and evaporation. A chromatography on silicagel (95/5 dichloromethane/ethanol) gives the expected compound (0.04 g).LC-MS: MH+=299. ¹H NMR (500 MHz, δ ppm) DMSO D6: 2.13 (s, 3H), 3.08 (t,2H), 3.46 (m, 2H), 3.52 (m, 2H), 3.70 (m, 4H), 4.54 (t, 2H), 7.23 (t,1H), 7.43 (d, 1H), 7.68 (d, 1H).

EXAMPLE 122-[4-(4-Pyridyl)piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-onedihydrochloride (R1=R2=R2′=H, R3=-, R4=4-pyridyl, X=N, n=m =1) (compound23)

The intermediate described in point 1.1 (0.2 g, 0.969 mmol), TGME (1mL), lutidine (125 μL, 0.969 mmol), cesium fluoride (0.148 g, 0.969mmol) and a solution of 1-(4-pyridyl)piperazine (0.238 g, 1.02 mmol) inTGME (1 mL) are successively introduced into a round-bottomed flaskfitted with a condenser, with magnetic stirring. The reaction medium isheated at 140° C. for 1 hour 50 minutes and allowed to cool, saturatedsodium carbonate solution and solid sodium chloride are added and themixture is extracted twice with ethyl acetate. The organic phases arewashed twice with saturated sodium chloride solution, dried over sodiumsulphate, filtered and concentrated. The residue obtained ischromatographed on silica gel (95/5/0.5 dichloromethane/methanol/NH₄OH)to give the expected compound in the form of a white solid (0.071 g).LC-MS: MH+=334. ¹H NMR (360 MHz, δ ppm) DMSO D6: 3.01 (t, 2H), 3.58 (m,8H), 4.51 (t, 2H), 6.91 (d, 2H), 7.18 (t, 2H), 7.37 (d, 1H), 7.63 (d,1H), 8.20 (d, 2H).

EXAMPLE 13:2-(4-Benzylpiperidin-1-yl)-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-onedihydrochloride (R1=R2=R2′=R3=H, R4=benzyl, X=C, n=m=1) (compound 1)

The intermediate described in point 1.1 (0.206 g, 1 mmol) dissolved inanhydrous toluene (8 mL), potassium tert-butoxide (0.157 mg, 1.4 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.04 g, 0.06 mmol),palladium(II) acetate (0.009 g, 0.04 mmol) and a solution ofN-benzylpiperazine (0.21 g, 1.2 mmol) in toluene (2 mL) are successivelyintroduced into a round-bottomed flask fitted with a condenser, withmagnetic stirring and under a nitrogen atmosphere. The reaction mixtureis heated at 85° C. overnight, allowed to cool, diluted with ethylacetate and washed successively with water (3 times) and with saturatedsodium chloride solution, dried over sodium sulphate, filtered andconcentrated. The residue is chromatographed (0.24 g, 8/2dichloromethane/ethyl acetate) to give the expected product (0.075 g).LC-MS: MH+=346. ¹H NMR (360 MHz, δ ppm) DMSO D6: 1.37 (m, 1H), 1.67(broad d, 1H), 1.80 (m, 1H), 2.58 (d, 1H), 2.84-3.00 (t, 2H and m, 1H),3.81 (broad d, 1H), 4.40 (t, 2H), 7.12 (t, 1H), 7.20 (m, 3H), 7.26-7.37(m, 1H and d, 1H), 7.5 (d, 1H)

EXAMPLE 141-(6-Oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-4-phenyl-4-piperidinecarboxamide(R1=R2=R2′=H, R3=CONH₂, R4=phenyl, X=C, n=m=1) (compound 43)

14.1: Compound of formula (III): 4-phenylpiperidine-4-carboxamide

The compound is obtained according to the synthesis described in theliterature: Bioorg. Med. Chem. Lett. 7(19), 1997, 2531-2536.

14.2:1-(6-oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-4-phenyl-4-piperidinecarboxamide

300 mg of compound (II) described in point 1.1, 5 mL ofdimethylformamide, 70 mg of potassium fluoride, 0.2 mL of 2,6-lutidineand 510 mg of compound (IV) described above are introduced into a 50 mLthree-necked flask under nitrogen. The mixture is stirred for 4 hours at140° C. and then evaporated under high vacuum. The residue obtained ischromatographed on silica gel (70-200 microns) with a mixture of 2%methanol in dichloromethane. The product obtained is then recrystallizedfrom a minimum amount of hot acetone. 270 mg of white crystals areobtained. The signals in the NMR spectrum correspond to the expectedproduct: ¹H NMR (200 MHz, δ ppm) DMSO D6: 2.0 (m, 2H), 2.5 (m, 2H), 3.0(t, 2H), 3.2-3.8 (m, 4H), 4.45 (t, 2H), 7.0-7.5 (m, 10H)

EXAMPLE 151-(6-Oxo-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)-4-phenyl-4-aminopiperidinedihydrochloride (R1=R2=R2′=H, R3=NH₂, R4=phenyl, X=C, n=m =1) (compound46)

4 mL of concentrated aqueous hydrochloric acid solution are added tocompound 42 from the table (0.53 g, 1.21 mmol), manufactured accordingto the methods described above, predissolved in 5 mL of methanol andmaintained under magnetic stirring at room temperature for 30 minutes.The mixture is concentrated under vacuum and the residue is taken up inabsolute ethanol and then re-evaporated to dryness. The expectedcompound is obtained in the form of a white solid (0.45 g). ¹H NMR (200MHz, δ ppm) DMSO D6: 2.4-2.8 (m, 4H), 3.1 (t, 2H), 3.7 (m, 2H), 4.2 (m,2H), 4.8 (t, 2H), 7.4-7.8 (m, 8H), 9.0 (s, 2H).

EXAMPLE 162-[4-(4-Hydroxyphenyl)-piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(R1=R2=R2′=H, R3=-, X=N, R4=4-hydroxyphenyl, n=m=1) (compound 71)

16.1. 2-Chloro-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one ethylene ketal

A solution of the intermediate described in point 1.1 (0.6 g, 2.9 mmol)in 1,2-dichloroethane (10 mL), ethylene glycol (0.216 g, 3.49 mmol),p-toluenesulphonic acid (0.01 g) and trimethyl orthoformate (0.372 g,3.49 mmol) are successively introduced into a round-bottomed flaskfitted with a condenser, with magnetic stirring, and the mixture iscompleted with 13 mL of 1,2-dichloroethane. The resulting mixture isrefluxed for 24 hours, the same amounts of the reagents (ethyleneglycol, p-toluenesulphonic acid and trimethyl orthoformate) are addedand the mixture is heated for a further 18 hours. After evaporation ofthe solvent, the residue is taken up in ethyl acetate and washed withdilute sodium carbonate solution and then with water, and the organicphase is dried and evaporated to dryness. The residue is chromatographedon silica gel (gradient: pure dichloromethane to 96/4dichloromethane/ethyl acetate) to give the title compound (0.54 g, 74%).MH+=251.

16.2. Preparation of2-[4-(4-benzyloxyphenyl)piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-oneethylene ketal

The intermediate described in point 16.1 (0.54 g, 2.16 mmol), TGME (3mL), lutidine (277 μL, 2.38 mmol), cesium fluoride (0.328 g, 2.16 mmol)and 1-(4-benzyloxyphenyl)piperazine (0.725 g, 2.38 mmol) aresuccessively introduced into a round-bottomed flask fitted with acondenser, with magnetic stirring. The reaction medium is heated at 100°C. for 3 hours, lutidine is added (300 μL, 2.57 mmol) and the mixture isheated at 120° C. for 8 hours. The mixture is cooled, water is added andthe resulting mixture is extracted twice with ethyl acetate. The organicphases are washed twice with water, dried over sodium sulphate, filteredand concentrated. The residue obtained is purified by chromatographytwice on silica gel (gradient from 90/10 dichloromethane/ethyl acetateto 40/60 dichloromethane/ethyl acetate, and then gradient from ethylacetate to 95/5 ethyl acetate/methanol) to give the expected compoundcontaminated with about 50% ketone originating from the hydrolysis ofthe ketal function (0.365 g). LC-MS: MH+=483, MH+=439.

16.3. Preparation of2-[4-(4-hydroxyphenyl)-piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-oneethylene ketal

The mixture of compounds from Example 16.2 (0.365 g), ethanol (60 mL),dichloromethane (about 0.5 mL) and 10% palladium-on-charcoal (0.04 g)are introduced into a round-bottomed flask and maintained under magneticstirring and under a hydrogen atmosphere for 17 hours at roomtemperature. After filtration and evaporation of the solvent, theresidue is chromatographed on silica gel (gradient from dichloromethaneto 94/6 dichloromethane/methanol) to give the title product (0.132 g).¹H NMR (300 MHz, δ ppm) DMSO D6:2.2 (t, 2H), 3.13 (m, 4H), 3.46 (m, 3H),4.08-4.20 (m, 4H), 4.21 (t, 2H), 6.68 (dd, 2H), 6.86 (dd, 2H), 7.04 (m,2H), 7.32 (m, 1H), 8.91 (s, 1H).

16.4. Preparation of2-[4-(4-hydroxyphenyl)-piperazin-1-yl]-4,5-dihydroimidazo[4,5,l-ij]quinolin-6-one

2-[4-(4-Hydroxyphenyl)piperazin-1-yl]-4,5-dihydroimidazo[4,5,1-ij]quinolin-6-one(0.055 g, 0.14 mmol) is dissolved in 11 mL of tetrahydrofuran and 3.6 mLof aqueous 5% hydrochloric acid solution are added. The mixture is leftunder magnetic stirring for 16 hours at room temperature and then at 50°C. for 2 hours. After dilution with water, the mixture is basified withsodium bicarbonate, extracted twice with ethyl acetate and the organicphases are dried over sodium sulphate. After the usual work-up, theresidue is purified by chromatography on silica gel (gradient fromdichloromethane to 94/6 dichloromethane/methanol) to give the titleproduct (0.027 g, 55%). ¹H NMR (500 MHz, δ ppm) DMSO D6: 2.99 (t, 2H),3.13 (m,4H), 3.53 (m, 4H), 4.47 (t, 2H), 6.67 (d, 2H), 6.85 (d, 2H) 7.15(t, 1H), 7.34 (d, 1H), 7.60 (d, 1H), 8.88 (s, 1H).

EXAMPLE 172-[4-(4-Fluorophenyl)piperazin-1-yl]-4,5-dihydro-9-methylimidazo[4,5,1-ij]quinolin-6-one(R1=9-CH₃, R2=R2′=H, R3=-, X=N, R4=4-fluorophenyl, n=m=1) (compound 84)

The intermediate described in point 1.4 (0.2 g, 0.907 mmol), TGME (2mL), lutidine (0.116 mL, 0.998 mmol), cesium fluoride (0.138 g, 0.907mmol) and 4-fluorophenylpiperazine (0.180 g, 0.998 mmol) aresuccessively introduced into a round-bottomed flask fitted with acondenser, with magnetic stirring. The reaction mixture is heated at140° C. for 3 hours and allowed to cool, water is added and the mixtureis extracted twice with ethyl acetate. The organic phases are washedtwice with water, dried over sodium sulphate, filtered and concentrated.The residue obtained is chromatographed on silica gel (gradient frompure dichloromethane to 98/2 dichloromethane/methanol) to give theexpected compound in the form of a white solid (0.206 g, 62%). ¹H NMR(500 MHz, δ ppm) DMSO D6: 2.50 (s, 3H), 2.97 (t, 2H), 3.28 (m, 4H), 3.54(m, 4H), 4.45 (t, 2H), 7.05 (m, 5H), 7.29 (d, 1H).

EXAMPLE 181-[4-(4-Fluorophenyl)-piperazin-1-yl]-3-methyl-8,9-dihydro-7H-2,9a-diazabenzo[cd]azulen-6-one (R1=3-CH₃, R2=R2′=H, R3=-, X=N,R4=4-fluorophenyl, n=2, m=1) (compound 85)

1-Chloro-3-methyl-8,9-dihydro-7H-2,9a-diazabenzo[cd]azulen-6-one (0.2 g,0.852 mmol), TGME (2 mL), lutidine (0.109 mL, 0.937 mmol), cesiumfluoride (0.130 g, 0.852 mmol) and 4-fluorophenylpiperazine (0.169 g,0.937 mmol) are successively introduced into a round-bottomed flaskfitted with a condenser with magnetic stirring. The reaction mixture isheated at 140° C. for 3.5 hours and allowed to cool, water is added andthe mixture is extracted twice with ethyl acetate. After the usualwork-up, the residue obtained is chromatographed on silica gel (gradientfrom pure dichloromethane to 60/40 dichloromethane/ethyl acetate) togive the title compound in the form of a white solid (0.137 g, 42%). ¹HNMR (500 MHz, δ ppm) DMSO D6: 2.20 (m, 2H), 2.53 (s, 3H), 3.04 (m, 2H),3.30 (m, 4H), 3.40 (m, 4H), 4.25 (m, 2H), 7.07 (m, 5H), 7.61 (d, 1H).

EXAMPLE 192-[4-(4-Fluorophenyl)piperazin-1-yl]-4,5-dihydro-7-methylimidazo[4,5,1-ij]quinolin-6-one(R1=7-CH₃, R2=R2′=H, R3=-, X=N, R4=4-fluorophenyl, n=m =1) (compound 83)

2-Chloro-4,5-dihydro-7-methylimidazo[4,5,1-ij]quinolin-6-one (0.245 g,1.1 mmol), TGME (2.5 mL), lutidine (0.161 mL, 1.21 mmol), cesiumfluoride (0.167 g, 1.1 mmol) and 4-fluorophenylpiperazine (0.219 g, 1.1mmol) are successively introduced into a round-bottomed flask fittedwith a condenser, with magnetic stirring. The reaction mixture is heatedat 140° C. for 2.5 hours and allowed to cool, water is added and themixture is extracted twice with ethyl acetate. After the usual work-up,the residue obtained is chromatographed on silica gel (gradient from80/20 dichloromethane/ethyl acetate to 40/60 dichloromethane/ethylacetate) to give the title compound in the form of a white solid (0.26g, 65%). ¹H NMR (500 MHz, δ ppm) DMSO D6: 2.59 (s, 3H), 2.98 (t, 2H),3.26 (m, 4H), 3.49 (m, 4H), 4.42 (t, 2H), 6.94 (d, 1H), 7.05 (m, 4H),7.50 (d, 1H).

EXAMPLE 202-[4-(4-Fluorophenyl)piperazin-1-yl]-4,5-dihydro-8-methylimidazo[4,5,1-ij]quinolin-6-one(R1=8-CH₃, R2=R2′=H, R3=-, X=N, R4=4-fluorophenyl, n=m=1) (compound 82)

The title compound is obtained from a ½mixture of2-chloro-4,5-dihydro-8-methylimidazo[4,5,1-ij]quinolin-6-one and2-chloro-4,5-dihydro-7-methylimidazo[4,5,l-ij]quinolin-6-one, using theconditions described in Example 19. After chromatography on silica gel,two successive crystallizations gave the desired isomer contaminatedwith only 4% of the other isomer (0.053 g, yield calculated on the goodisomer: 48%). ¹H NMR (500 MHz, δ ppm) DMSO D6: 2.40 (s, 3H), 2.98 (t,2H), 3.26 (m, 4H), 3.55 (m, 4H), 4.45 (t, 2H), 7.06 (m, 4H), 7.18 (s,1H), 7.44 (s, 1H).

EXAMPLE 212-[4-(4-Fluorophenyl)piperazin-1-yl]-4,5-dihydro-7-methoxyimidazo[4,5,1-ij]quinolin-6-one(R1=7-OCH₃, R2=R2′=H, R3=-, X=N, R4=4-fluorophenyl, n=m=1) (compound 81)

The title compound is obtained from2-chloropiperazin-1-yl-4,5-dihydro-7-methoxyimidazo[4,5,l-ij]quinolin-6-oneusing the conditions described in Example 19 (29%). ¹H NMR (500 MHz, δppm) DMSO D6: 2.89 (t, 2H), 3.26 (m, 4H), 3.44 (m, 4H), 3.81 (s, 3H),4.36 (t, 2H), 6.79 (d, 1H), 7.06 (m, 4H), 7.58 (d, 1H).

The table which follows illustrates the chemical structures and thephysical properties of a number of compounds of the inventioncorresponding to the general formula (I). Depending on whether n=1 or 2in this formula, two compounds of formula (I) have been representedbelow with, for each of them, the numbering of the atoms on thebenzimidazole nucleus.

In this table:

-   -   HCl represents a hydrochloride and CF₃CO₂H represents a        trifluoroacetate salt, while “−” represents a compound in free        form,    -   Me, Et, n-Pr and tBu represent, respectively, methyl, ethyl,        n-propyl and tert-butyl groups,    -   Bn and Ph represent, respectively, benzyl and phenyl groups,

except where otherwise mentioned, the NMR analyzes correspond to protonNMRs and the measurements are carried out in d₆-DMSO. * and ** mean thatthe measurements are carried out, respectively, at 360 MHz and at 500MHz. If no indication of this type is given, then the measurement iscarried out at 200 MHz. TABLE

(I) with n = 1 (I) with n = 2 No. R1 R2 R2′ R3 R4 X n M Salt NMR 1 H H HH Bn C 1 1 — 1.37(m,1H), 1.67(broad d,1H), 1.80(m,1H), 2.58(d,1H),2.84-3.00(t,2H and m,1H), 3.81(broad d,1H), 4.40(t,2H), 7.12(t,1H),7.20(m,3H), 7.26-7.37(m,1H and d,1H), 7.5(d,1H)* 2 H H H — Ph N 1 1 —3.0(t,2H), 3.35(m,4H), 3.58(m,4H), 4.5 (t,2H), 6.82(t,1H), 7.0(d,2H),7.15(t,1H), 7.25(t,2H), 7.38(d,1H), 7.62(d,1H)* 3 H H H —

N 1 1 — 3.03(t,2H), 3.55(m,4H), 3.70(m,4H), 4.51 (t,2H), 6.69(t,1H),6.90(d,1H), 7.16(t,1H), 7.37(d,1H), 7.60(m,2H), 8.15(d,1H)* 4 H H H —

N 1 1 — 3.02(t,2H), 3.50(m,4H), 3.95(m,4H), 4.50 (t,2H), 6.69(t,1H),7.15(t,1H), 7.35(d,1H), 7.62(d,1H), 8.41(d,2H)* 5 H H H —

N 1 1 — 3.01 Ct,2H), 3.52(m,4H), 3.88(m,4H), 4.49 (t,2H),6.67(s,1H),7.06(d,1H), 7.18(t,1H), 7.34(d,1H), 7.63(d,1H), 7.89(s,1H)* 6 H H H —

N 1 1 — 2.31(s, 3H), 3.03(m,4H), 3.59(m,4H), 4.49 (t,2H), 6.99(t,1H),7.07(d,1H), 7.18(m,3H), 7.36(d,1H), 7.52(d,1H)* 7 H H H —

N 1 1 — 3.01(t,2H), 3.48(m,4H), 3.58(m,4H), 4.49(t,2H), 6.81(d,1H),6.98(d,1H), 7.03(s,1H), 7.16(t,1H), 7.26(t,1H), 7.35(d,1H), 7.62(d,1H)*8 H H H —

N 1 1 — 2.35(s,3H), 3.08(t,2H), 3.11(m,4H), 3.65 (m,4H), 4.56(t,2H),7.13(m,2H), 7.24(t,1H), 7.29(d,1H), 7.43(d,1H), 7.68(d,1H)** 9 H H H —

N 1 1 — 3.09(t,2H), 3.68(m,4H), 3.75(m,4H), 4.58 (t,2H), 7.17(d,2H),7.24(t,1H), 7.44(d,1H), 7.69(d,1H), 8.17(d,2H)** 10 H H H —

N 1 1 — 3.08(t,2H), 3.39(m,4H), 3.64(m,48), 4.56 (t,2H), 7.10(d,28),7.24(t,1H), 7.34(d,2H), 7.43(d,18), 7.69(d,1H)** 11 H H H — Bn N 1 1 —2.63(m,48), 3.05(t,2H), 3.50(m,48), 3.63 (s,1H), 4.93(t,2H), 7.21(t,1H),7.35(m,1H), 7.42(m,5H), 7.65(d,1H)** 12 H H H —

N 1 1 — 1.51(s,9H), 3.07(t,2H), 3.46(m,4H), 3.58 (m,48),4.52(t,2H),7.23(t,1H), 7.43(d,1H), 7.68(d,1H)** 13 H H H H H N 1 1 2HCl 3.12(t,2H),3.95(m,4H), 3.94(m,4H), 4.66 (t,2H), 7.43(t,1H), 7.61(d,1H), 7.80(d,1H),9.63(s,2H)** 14 H H H —

N 1 1 — 3.00(t,2H), 3.17(m,4H), 3.58(m,4H), 4.44 (t,2H), 7.21(t,1H),7.41(d,1H), 7.65(d,1H), 7.75(m,2H), 7.84(m,3H)** 15 H H H — —COMe N 1 1— 2.13(s,3H), 3.08(t,2H), 3.46(m,2H), 3.52 (m,2H), 3.70(m,4H),4.54(t,2H), 7.23(t,1H), 7.43(d,1H), 7.68(d,1H)** 16 H H H — —CH₂COOEt N1 1 — 1.2(t,3H), 2.7(m,2H), 2.97(t,2H), 3.32 (s,2H), 3.41(m,2H),4.43(t,2H), 7.12(t,1H), 7.32(d,1H), 7.59(d,1H)* 17 H H H —

N 1 1 — 3.1(t,2H), 3.29(m,4H), 3.58(m,4H), 4.50 (t,2H), 7.05(m,4H),7.17(t,1H), 7.35(d,1H), 7.62(d,1H)* 18 H H H —

N 1 1 — 3.05(t,2H), 3.22(m,4H), 3.56(m,4H), 3.90 (s,3H), 4.50(t,2H),6.85(d,2H), 6.98(d,2H), 7.16(t,1H), 7.25(d,1H), 7.62(d,1H)* 19 H H H —

N 1 1 — 1.13(m,5H), 1.56(m,1H), 1.76(m,4H), 2.31 (m,1H), 2.69(m,4H),2.98(t,2H), 3.40 (m,4H), 4.42(t,2H), 7.15(t,1H), 7.32(d,1H), 7.68(d,1H)*20 H H H —

N 1 1 — 2.21(s,1H), 3.01(t,2H), 3.28(m,4H), 3.55 (m,4H), 4.49(t,2H),6.92(d,2H), 7.07(d,2H), 7.16(t,1H), 7.36(d,1H), 7.53(d,1H)* 21 H H H —

N 1 1 — 3.01(t,2H), 3.18(m,4H), 3.60(m,4H), 4.50 (t,2H), 7.09(t,1H),7.15(t,1H), 7.21(d,1H), 7.35(m,2H), 7.45(d,1H), 7.62(d,1H)* 22 H H H —

N 1 1 — 3.02(t,2H), 3.41(m,4H), 3.56(m,4H), 4.52 (t,2H), 7.01(d,1H),7.16(t,1H), 7.22(s,1H), 7.38(d,1H), 7.62(d,1H)* 23 H H H —

N 1 1 — 3.01(t,2H), 3.58(m,8H), 4.51(t,2H), 6.91 (d,2H), 7.18(t,2H),7.37(d,1H), 7.63(d,1H), 8.20(d,2H)* 24 H H H H Me N 1 1 2HCl 2.84(s,3H),3.08(t,2H), 3.27(m,≅2H), 3.55 (m,≅2H) 3.72(m,≅2H), 4.14(m,≅2H), 4.59(t,2H), 7.35(t,1H), 7.52(d,1H), 7.75(d,1H), 11.42(s,1H)* 25 H H H H Et N1 1 2HCl Presence of 2 conformers, ˜70/30: 1.32(t,3H), 2.31(t,0.6H),3.08(t,1.4H), 3.19(t,2H), 3.60, 3.74, 3.89, 4.12, 4.24(manymultiplets,8H), 4.35(t,0.6H), 4.55(t,1.4H), 7.36(m,1.4H), 7.50(m,0.9H),7.73(d,0.7H), 11.28(s,0.7H), 11.55(s,0.3H)* 26 H H H H n-Pr N 1 1 2HCl0.94(t,3H), 1.78(m,2H), 3.08(m,4H), 3.28 (m,2H), 3.62(3,2H), 3.88(m,2H),4.25 (m,2H), 4.65(t,2H), 7.42(t,1H), 7.60(d,1H), 7.76(d,1H),11.66(s,1H)* 27 H H H —

N 2 1 — 1.30-1.60(m,6H), 1.70(m,2H), 1.85(m,2H), 2.20(m,2H),2.40-2.60(m,3H), 2.90(t,2H), 3.05(m,2H), 3.65(d,2H), 4.20(m,2H), 7.20(t,1H), 7.65(d,1H), 7.70(d,1H)* 28 H H H H

C 2 1 — 1.10(d,1H), 1.20(m,4H), 1.60(d,1H), 1.80 (d,4H), 2.20(s,2H),2.30(s,1H), 2.70(m,4H), 3.05(dd,2H), 3.20(s,4H), 4.20(s,2H), 7.20(t,1H), 7.65(d,1H), 7.70(d,1H)* 29 H H H H Me N 1 2 — 1.96(m,2H),2.29(s,3H), 2.56(m,2H), 2.74 (m,2H), 2.99(t,2H), 3.73(m,4H), 4.49(t,2H),7.08 (t,1H), 7.22(d,1H), 7.43(d,1H)* 30 H H H —

N 1 1 — 3.01(t,2H), 3.29(broad s,4H), 3.58 (broad s,4H), 4.49(t,2H),6.98(d,2H), 7.16 (t,1H), 7.35(d,1H), 7.48(d,2H), 7.61(d,1H), 8.2(s,1H),9.98(s,1H)* 31 H H H — —COMe N 1 2 — Presence of 2 conformers, ˜60/40:1.36(m,0.8H), 1.54 (m,1.2H), 2.03(s,3H), 3.04(broad t,2H), 3.55(m,2H),3.78(m,2H), 3.89(m,2H), 7.31(m,1H), 7.45(m,1H), 7.6(m,1H)* 32 H Me H —Ph N 1 1 — 1.23(d,3H), 3.19(m,1H), 3.32(m,4H), 3.57 (m,4H), 4.11(t,1H),4.63(dd,1H), 6.81(t,1H), 7.01(d,2H), 7.17(t,1H), 7.26(t,2H), 7.37(d,1H), 7.61(d,1H)* 33 H Me H —

N 1 1 — 1.22(d,3H), 3.18(m,1H), 3.52(m,4H), 3.68 (m,4H), 4.12(t,1H),4.62(dd,1H), 6.69 (dd,1H), 6.9(d,1H), 7.17(t,1H), 7.36(d,1H),7.57(m,1H), 7.6(t,1H) 8.14(d,1H)* 34 H H H —

N 1 1 — 3.02(t,2H), 3.41(m,4H), 3.59(m,4H), 4.51 (t,2H), 7.18(t,1H),7.26(m,1H), 7.35(d,1H), 7.41(m,1H), 7.62(d,1H), 8.06(d,1H), 8.39(s,1H)*35 H H H — Ph N 2 1 — 2.2(m,2H), 3.05(m,2H), 3.30(m,4H), 3.35 (m,4H),4.25(m,2H), 6.8(t,1H), 7.0(d,2H), 7.2(t,1H), 7.25(d,1H), 7.3(d,1H), 7.6(d,1H), 7.65(d,1H)* 36 H H H H H C 1 1 — 1.6(s,6H), 2.9(t,2H),3.35(m,4H), 4.40 (t,2H), 7.10(t,1H), 7.3(d,1H), 7.55(d,1H) 37 H H H H PhC 1 1 — 1.95(m,4H), 2.85(m,1H), 3.20(m,4H), 4.0 (d,2H), 4.5(m,2H),7.2-7.4(m,7H), 7.65(d,1H) 38 H H H —CO— H C 1 1 — 1.75(m,4H), 2.3(m,1H),2.95(m,4H), 3.80 NH₂ (d,2H), 4.4(t,2H), 6.80(s,1H), 7.10(t,1H),7.25(d,2H), 7.55(d,1H) 39 H H H —OH Ph C 1 1 — 1.6(d,2H), 2.05(m,2H),2.90(t,2H), 3.2-3.8 (m,4H), 4.4(t,2H), 5.05(s,1H), 7-7.6(m,8H) 40 H H HNH— Ph C 1 1 — 1.8(m,2H), 1.85(s,3H), 2.4-2.6(m,2H), 3 COMe (m,2H),3.6(m,2H), 3.90(m,2H), 4.70(t,2H), 7-7.6(m,8H) 41 H H H —CH₂— Ph C 1 1 —2.1(m,2H), 2.3(m,2H), 3.0(t,2H), 3.3-3.5 OH (m,4H), 3.95(m,2H),4.60(t,2H), 7.2-7.8 (m,8H) 42 H H H —NH— Ph C 1 1 — 1.1(s,9H), 2(m,2H),2.5(m,2H), 2.90(t,2H), COtBu 3.2(m,2H), 3.70(m,2H), 4.4(t,2H), 7.1-7.4(m,8H), 7.55(d,1H) 43 H H H CONH₂ Ph C 1 1 — 2.0(m,2H), 2.5(m,2H),3.0(t,2H), 3.2-3.8 (m,4H), 4.45(t,2H), 7.0-7.5(m,10H) 44 H H H —NH— Ph C1 1 — 2.0-2.6(m,4H), 3.1(t,2H), 3.4(m,2H), 3.8 CONH2 (d,2H), 4.5(t,2H),5.5(s,2H), 6.6(s,1H), 7.2-7.6(m,7H), 7.7(d,1H) 45 H H H H

C 1 1 — 1.2-2.2(m,12H) 3.0(m,3H), 3.2-3.4(m,4H), 4.2(d,2H), 4.65(t,2H),7.4(t,1H), 7.6,(d,1H), 7.8(d,1H) 46 H H H —NH₂ Ph C 1 1 2HCl2.4-2.8(m,4H), 3.1(t,2H), 3.7(m,2H), 4.2 (m,2H), 4.8(t,2H),7.4-7.8(m,8H), 9.0(s,2H) 47 H H H H

C 1 1 — 1.5-2.0(m,8H), 3.0(m,4H), 3.2-3.6(m,5H), 4.1(d,2H), 4.6(t,2H),7.3(t,1H), 7.5(d,1H), 7.6(d,1H) 48 H H H H

C 1 1 — 1.5-2.0(m,10H), 2.1(d,2H), 2.8-3.0(m,4H), 3.1-3.6(m,3H),4.1(m,2H), 4.6(t,2H), 7.4(t,1H), 7.6(d,1H), 7.7(d,1H) 49 H Me Me — Ph N1 1 — 1.19(s,6H), 3.33(m,4H), 3.55(m,4H), 4.29 (s,2H), 6.81(t,1H),7.00(d,2H), 7.18(t,1H), 7.25(t,2H), 7.38(d,1H), 7.62(d,1H)** 50 H H H —

N 1 1 2HCl 3.06(t,2H), 3.63(m,4H), 3.84(m,4H), 4.65 (t,2H), 7.10(d,2H),7.26(d,2H), 7.36(dd,1H), 7.54(d,1H), 7.71(d,1H), 10.06(broad peak,2H)**51 H H H —

N 1 1 — 3.0(t,2H), 3.71(m,8H), 4.47(t,2H), 7.16 (dd,1H), 7.32(dd,2H),7.36(d,1H), 7.55 (dd,2H), 7.62(d,1H); ¹⁹F:51.6(m,1F)* 52 H H H —

N 1 1 — 3.0(t,2H), 3.44(m,4H), 3.56(m,2H), 3.83 (m,2H), 4.48(t,2H),7.16(dd,1H), 7.36 (d,1H), 7.47(d,2H)* 53 H H H —

N 1 1 — 0.88(t,3H), 1.30(m,4H), 1.53(m,2H), 2.37 (t,2H), 3.01(t,2H),3.41(m,2H), 3.44 (m,2H), 3.64(m,4H), 4.47(t,2H), 7.16(dd,1H),7.35(d,1H), 7.61(d,1H)* 54 H Me H H

C 1 1 — Presence of 2 conformers. 1.21(d,3H), 1.74 m,2H), 1.94(m,2H),2.14(m,3H), 2.80 (m,1H), 3.13(m,3H), 3.95(m,2H), 4.11 (t,1H),4.58(m,1H), 7.15 (dd,1H), 7.35 (m,2H), 7.59(d,1H), 11.57(m,1H)* 55 H H HH

C 2 1 — Presence of 2 conformers. 1.75(m,2H), 1.95 (m,2H), 2.12(2s40/60,3H), 2.23(m,2H) 2.79,(2m 40/60,1H), 3.05(m,4H), 3.65 (m,2H),4.24(m,2H), 7.19(dd,1H), 7.36 (s,1H), 7.68(m,2H), 11.54(2s,40/60,1H)* 56H H H —

N 1 1 — 2.58(t,2H), 2.62(m,4H), 2.78(t,2H), 2.98 (t,2H), 3.42(m,4H),4.43(t,2H), 7.14 (dd,1H), 7.19(m,1H), 7.26(m,4H), 7.33 (d,1H),7.56(d,1H)** 57 H H H —

N 1 1 — 1.45(s,9H), 3.00(t,2H), 3.22(m,4H), 3.55 (m,4H), 4.47(t,2H),6.91(d,2H), 7.15 (dd,1H), 7.33(m,2H), 7.35(d,1H), 7.61(d,1H)** 58 H H H—

N 1 1 — 2.79(s,6H), 3.0(t,2H), 3.14(m,4H), 3.55 (m,4H), 4.47(t,2H),6.71(d,2h), 6.91(d,2H), 7.15(dd,1H), 7.35(d,1H), 7.60(d,1H)** 59 H H H —

N 1 1 — 1.69(tt,1H), 2.13(s,6H), 2.22(t,2H), 2.22 (t,2H), 3.00(t,2H),3.27(m,4H), 3.55(m,4H), 4.48(t,2H), 6.94(d,2H), 7.15(dd,2H), 7.35(d,1H), 7.46(d,2H), 7.61(d,1H) 9.68(s,1H)** 60 H H H —

N 1 1 — 1.99(s,3H), 3.00(t,2H), 3.25(m,4H), 3.55 (m,4H), 4.48(t,2H),6.94(d,2H), 7.15 (dd,1H), 7.35(d,1H), 7.44(d,2H), 7.61 (d,1H),9.70(s,1H)** 61 H H H —OH

C 1 1 — 1.5—1.7(d,2H), 2.0-2.1(d,2H), 2.9(t,2H), 3.3-3.5(t,2H),2.7-2.8(d,2H), 4.4(t,2H), 5.2(s,1H), 7.0-7.6(m,7H) 62 H H H —OH

C 1 1 — 1.6-1.8(m,2H), 2.1-2.3(m,2H), 2.9(t,2H), 3.3-3.5(t,2H),3.6-3.8(d,2H), 4.4(t,2H) 5.4(s,1H), 7.0-8.0(m,7H) 63 H H H H Ph C 1 2 —1.6-2.2(m,6H), 2.6-4(m,8H), 4.8(m,1H), 7.1-7.3(m,5H), 7.4(t,1H),7.6(m,2H) 64 H H H —CO—NH₂

C 1 1 2 CF₃CO₂H 1.2—2.4(m,8H), 2.6-3.7(m,10H), 4.2(d,2H), 4.7(t,2H),7.4(t,1H), 7.6(d,1H), 7.8(d,1H), 8.2(d,2H) 65 H H H —

N 1 1 — 3.01(t,2h), 3.20(m,4H), 3.59(m,4H), 4.48 (t,2H), 7.01(m,1H),7.14(m,4H), 7.36(d,1H), 7.62(d,1H) 66 H H H —

N 1 1 — 3.01(t,2H), 3.15(m,4H), 3.58(m,4H), 4.48 (t,2H), 7.03(m,1H),7.15(m,2H), 7.24 (m,1H), 7.36(d,1H), 7.62(d,1H) 67 H H H —

N 1 1 — 3.01(t,2H), 3.54(m,4H), 3.76(m,4H), 4.49 (t,2H), 7.15(t,1H),7.35(d,1H), 7.61(d,1H), 7.88(d,1H),8.12(d,1H), 8.39(s,1H) 68 H H H —

N 1 1 — 2.56(m,4H), 2.96(t,2H), 3.43(m,4H), 3.59 (s,2H), 4.41(t,2H),7.13(t,1H), 7.32(d,1H), 7.35(d,2H), 7.58(d,1H), 8.52(d,2H) 69 H H H —

N 1 1 — 2.32(s,3H), 3.00(t,2H), 3.51(m,4H), 3.66 (m,4H), 4.49(t,2H),6.55(d,1H), 6.67(d,1H), 7.15(t,12H), 7.35(d,1H), 7.46(t,1H), 7.61(d,1H)70 H H H —

N 1 1 — 1.43(m,2H), 1.50(m,6H), 1.61(m,2H), 1.74 (m,2H), 2.49(m,1H),2.62(m,4H), 2.97 (t,2H), 3.37(m,48), 4.41(t,2H), 7.12 (t,1H),7.32(d,1H), 7.57(d,1H) 71 H H H —

N 1 1 — 2.99(t,2H), 3.13(m,48), 3.53(m,48), 4.47 (t,2H), 6.67(d,2H),6.85(d,2H), 7.15 (t,1H), 7.34(d,1H), 7.60(d,1H), 8.88(s,1H) 72 H H H —

N 1 1 — 2.62(m,6H), 2.99(m,48), 3.422(m,4H), 4.43(t,2H), 6.92(m,2H),7.14(t,1H), 7.32 (m,2H), 7.58(d,1H) 73 H H H —

N 1 2 — 2.34(m,2H), 3.12(m,48), 3.67(m,8H), 4.20 (m,2H), 4.67(m,2H),7.30(m,68), 7.53 (m,1H), 7.68(m,1H), 11.37(m,1H) 74 H H H —

N 1 1 — 1.47(m,2H), 1.60(m,2H), 2.36(t,2H), 2.50 (m,4H), 2.60(t,2H),2.98(t,2H), 3.39(m,4H), 4.42(t,2H), 7.14(t,1H), 7.16-7.30(m,5H),7.33(d,1H), 7.58(d,1H) 75 H H H —

N 1 1 — 1.79(m,2H), 2.35(m,2H), 2.54(m,4H), 2.64 (t,2H), 2.98(t,2H),3.41(m,4H), 4.42 (t,2H), 7.14(t,1H), 7.26(d,2H), 7.33(d,1H), 7.58(d,1H), 8.45(d,2H) 76 H H H —NH₂ H C 1 1 HCl 1.6-2.2(m,4H), 3.0(t,2H),3.5(m,3H), 4.1 (d,2H), 4.6(t,2H), 7.4(t,1H), 7.6(d,1H), 7.75(d,1H),8.5(s,2H) 77 H H H H

C 1 1 — 1.92(m,4H), 2.9(m,1H), 3.0-3.2(m,5H), 4.0(d,2H), 4.45(t,2H),7.2(t,1H), 7.3(m,4H), 7.6(d,1H), 8.5(d,2H) 78 H H H —

N 1 1 — 1.39(m,1H), 1.72(m,2H), 1.83(m,2H), 2.12 (s,3H), 2.19(m,1H),2.64(m,4H), 2.78 (m,2H), 2.97(t,2H), 3.39(m,4H), 4.41(t,2H), 7.13(t,1H),7.32(d,1H), 7.56(d,1H) 79 H H H —

N 1 1 — 3.00(t,2H), 3.20(m,4H), 3.55(m,4H), 4.47 (t,2H), 5.03(s,2H),6.94(m,4H), 7.15(t,1H), 7.37(m,6H), 7.60(d,1H) 80 H H H —

N 1 1 — 1.76(m,2H), 2.34(t,2H), 2.53(m,4H), 2.61 (t,2H), 2.97(t,2H),3.39(m,4H), 4.42(t,2H), 7.14(m,2H), 7.21(m,2H), 7.27(m,2H), 7.32 (d,1H),7.57(d,1H) 81 7-OMe H H —

N 1 1 — 2.89(t,2H), 3.26(m,4H), 3.44(m,4H), 3.81 (s,3H), 4.36(t,2H),6.79(d,1H), 7.06(m,4H), 7.58(d,1H) 82 8-Me H H —

N 1 1 — 2.40(s,3H), 2.98(t,2H), 3.26(m,4H), 3.55 (m,4H), 4.45(t,2H),7.06(m,4H), 7.18(s,1H), 7.44(s,1H) 83 7-Me H H —

N 1 1 — 2.59(s,3H), 2.98(t,2H), 3.26(m,4H), 3.49 (m,4H), 4.42(t,2H),6.94(d,1H), 7.05(m,4H), 7.50(d,1H) 84 9-Me H H —

N 1 1 — 2.50(s,3H), 2.97(t,2H), 3.28(m,4H), 3.54 (m,4H), 4.45(t,2H),7.05(m,5H), 7.29(d,1H) 85 3-Me H H —

N 2 1 — 2.20(m,2H), 2.53(s,3H), 3.04(m,2H), 3.30 (m,4H), 3.40(m,4H),4.25(m,2H), 7.07 (m,5H), 7.61(d,1H) 86 H H H —N(— H C 1 1 — 2.2(m,2H),2.4(m,2H), 3.0(m,2H), 3.2 Me)₃ ⁺ (s,9H), 3.4(m,2H), 3.5(m,1H),4.5(m,2H), Cl⁻ 4.7(m,2H), 7.5(t,1H), 7.75(d,1H), 7.9(d,1H) 87 H H H —

N 1 1 — 1.10(m,2H), 1.30(s,9H), 1.65(m,2H), 2.4 (m,1H), 2.60(m,6H),3.0(t,2H), 3.4(m,4H), 3.95(m,2H), 4.4(t,2H), 7.1(t,1H), 7.25 (d,1H),7.6(d,1H) 88 H H H —

N 1 1 — 2.0(m,2H), 2.4(m,2H), 3.0-3.3(m,2H), 3.5 (m,3H) 4.0(m,2H),4.7(m,2H), 7.45(t,1H) 89 H H H —NH— H C 1 1 2 1.8(m,2H), 2.30(m,2H),2.75(s,3H), 3.2 Me CF₃CO₂H (m,2H), 3.5(m,1H), 3.45(m,2H), 4.2(m,2H),4.75(m,2H), 7.5(t,1H), 7.65(d,1H), 7.8(d,1H) 90 H H H —N— H C 1 1 21.75(m,2H), 2.10(m,2H), 2.65(s,6H), 3.4 (Me)₂ CF₃CO₂H (m,1H),3.25(m,2H), 4.15(m,2H), 4.60 (t,2H), 7.6(t,1H), 7.5(d,1H), 7.7(d,1H) 91H H H —OH

C 1 1 — 1.65(d,2H), 2.4(m,2H),3.10(t,2H), 3.5 (m,2H), 3.8(m,2H),4.5(t,2H), 5.45(s,1H), 7.1-7.4(m,3H), 7.6-7.9(m,3H), 8.6(d,1H)The compounds of the invention underwent pharmacological tests todetermine their inhibitory effect on PARP or poly(ADP-ribose)polymerase.

The compounds of the invention were subjected to the following test:

Effects of the Compounds on the Enzymatic Activity of PARP

Recombinant human PARP-1 (hPARP-1) is produced by the Sf9 cells using abaculovirus expression system (Giner et al., Gene (1992) 114 279-283).The enzyme is partially purified from the cell extract obtained afterprecipitation with 70% ammonium sulphate. The hPARP-1 solution obtainedis capable of generating 0.5-0.7 nmol of nicotinamide from NAD+ underthe standard test conditions described below. The test compounds aredissolved in an incubation medium containing 50 mM of Tris-HCl, 10 mM ofMgCl₂, 20 μM of zinc acetate, 1.5 mM of dithiothreitol, 0.2 μg ofhistone and 0.1 μg of oligonucleotide (GGAATTCC) per 100 μL, in thepresence of partially purified hPARP-1 buffered to pH8. The enzymaticreaction is initiated by addition of NAD+ (0.2 mM) and monitored at roomtemperature for 20 minutes. The reaction is stopped by the addition ofHClO₄ (1.2 M) at 4° C. After centrifugation, the supernatants areanalysed by HPLC (Shandon Ultrabase C8 column). Isocratic elution isperformed using a phosphate buffer (0.1 M) of pH 4.5 containing 6%acetonitrile, injected at 1.25 mL/min for 6 minutes. The nicotinamideformed is detected by measuring the UV absorbence of the eluate at 265nm and is quantified relative to the peak formed with an externalstandard of nicotinamide (2 nmol). The residual hPARP-1 activitymeasured in the presence of variable concentrations of compounds of theinvention is compared with that obtained in their absence. All themeasurements are carried out at least in duplicate, and the IC₅₀ valuesare calculated using the effect-dose sigmoid equation.

The compounds that are most active in this test are characterized byIC₅₀ values of between 5 and 500 nM.

Moreover, the compounds in accordance with the invention are also activetowards PARP-2, the compounds that are most active towards this enzymealso being characterized by IC₅₀ values of between 5 and 500 nM.

It thus appears that the compounds of the invention have selectiveinhibitory activity on PARP, in particular PARP-1 and PARP-2.

The compounds of the invention may thus be used for the preparation ofmedicinal products, in particular PARP-inhibiting medicinal products.These medicinal products find their use in therapy, in particular in theprevention or treatment of myocardial infarction, cardiac ischemia,cardiac insufficiency, atherosclerosis, restenosis after PTCA or bypass,cerebral ischemia and cerebral infarction, caused by an ischemia, atrauma or a thromboembolic accident, neurodegenerative diseases such asParkinson's disease, Alzheimer's disease and Huntington's chorea, acuterenal insufficiency, in particular that of ischemic origin or appearingafter kidney transplant, heart transplant: treatment of graft rejectionand accelerated atherosclerosis of grafts, inflammatory pathologies,immunological disorders, rheumatoid diseases, diabetes and pancreatitis,septic shock, acute respiratory distress syndrome, tumours andmetastases, autoimmune diseases, AIDS, hepatitis, psoriasis, vasculitis,ulcerative colitis, multiple sclerosis and myasthenia.

Thus, the compounds of formula (I) in accordance with the invention maybe used for the preparation of a medicinal product for treating andpreventing disorders in which the enzyme PARP is involved.

According to another aspect, a subject of the present invention is theuse of the compounds of formula (I) for which R1=R2=R2′=R3=H, X=C, n=m=1and R4 represents either a 4-imidazolyl group or a 5-methyl-4-imidazolylgroup, for the manufacture of a medicinal product for treating orpreventing disorders in which the enzyme poly(ADP-ribose) polymerase orPARP is involved, such as those mentioned above.

Finally, the present invention also relates to pharmaceuticalcompositions containing a compound according to the invention as activeprinciple. These pharmaceutical compositions contain an effective doseof a compound according to the invention, and also one or more suitablepharmaceutical excipients. The said excipients are chosen according tothe desired pharmaceutical form and mode of administration.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or the possible salt or hydratethereof, may be administered in a unit form of administration, mixedwith conventional pharmaceutical excipients, to animals and to humanbeings for the prophylaxis or treatment of the above disorders ordisease. The unit forms of administration that are appropriate compriseoral-route forms such as tablets, gel capsules, powders, granules andoral solutions or suspensions, sublingual, buccal, intratracheal andintranasal administration forms, subcutaneous, intramuscular orintravenous administration forms and rectal administration forms. Fortopical application, the compounds according to the invention may beused in creams, ointments or lotions.

The dose of active principle administered per day may range from 0.1 to1000 mg/kg via the oral, parenteral or rectal route. There may bespecial cases in which higher or lower doses are suitable, such dosesalso forming part of the invention. In usual practice, the dose which issuitable for each patient is determined by the doctor according to themode of administration and the weight and response of the said patient.

When a solid composition in the form of tablets is prepared, the mainactive ingredient is mixed with a pharmaceutical excipient, such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets may be coated with sucrose, a cellulose derivative orother materials. The tablets may be made by various techniques, such asdirect tabletting, dry granulation, wet granulation or hot-melting.

A preparation in the form of gel capsules is obtained by mixing theactive ingredient with a diluent and pouring the mixture obtained intosoft or hard gel capsules.

Aqueous suspensions, isotonic saline solutions or sterile and injectablesolutions which contain pharmacologically compatible dispersants and/orwetting agents, for example propylene glycol or butylene glycol, may beused for a parenteral administration.

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration of a compound according to the invention ora pharmaceutically acceptable salt thereof.

1. A compound corresponding to formula (I)

in which: R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogenatom, a nitro group or a C1-C4 alkoxy group, R2 and R2′ represent,independently of each other, a hydrogen atom or a C1-C4 alkyl group, Xrepresents a nitrogen atom or a carbon atom, n is equal to 1 or 2, m isequal to 1 or 2, and, when X represents a carbon atom: R3 represents ahydrogen atom, a group —NR5R6, a group —N(R5)₃ ⁺, a group —NHCOR7, agroup —CONHR5, a group —COR7, an —NHCONH₂ group, an —OH group or a—CH₂OH group, R4 represents a —(CH₂)_(p)-heteroaryl group, in which pmay range from 0 to 4 and in which the heteroaryl group is chosen froman imidazolyl group, optionally substituted with a C1-C4 alkyl group, ora pharmaceutically acceptable acid addition salt thereof, with theproviso that when R1=R2=R2′=R3=H, X=C, n=m=1, R4 is other than4-imidazolyl or 5-methyl-4-imidazolyl.
 2. A compound according to claim1, wherein: R1 represents a hydrogen atom, R2 and R2′ represent,independently of each other, a hydrogen atom or a C1-C4 alkyl group, Xrepresents a carbon atom, n is equal to 1 or 2, m is equal to 1, R3represents a hydrogen atom, a group —NR5R6, a group —N(R5)₃ ⁺, a group—NHCOR7, a group —CONHR5, an —NHCONH₂ group, an —OH group or a —CH₂OHgroup, R4 represents a heteroaryl group chosen from an imidazolyl group,optionally substituted with a C1-C4 alkyl group.
 3. A compound accordingto claim 2 wherein: R1 represents a hydrogen atom, R2 and R2′ represent,independently of each other, a hydrogen atom or a methyl group, Xrepresents a carbon atom, n is equal to 1 or 2, m is equal to 1, R3represents a hydrogen atom, a group —NR5R6, an —N(CH₃)₃ ⁺ group, a group—NHCOR7, a group —CONHR5, an —NHCONH₂ group, an —OH group or a —CH₂OHgroup, R4 represents a heteroaryl group chosen from an imidazolyl group,optionally substituted with a methyl group,.
 4. A process for preparinga compound according to claim 1 wherein a compound of formula (II):

in which R1, R2, R2′ and n are as defined in claim 1 and A represents aleaving group, is reacted with an amine of formula (III):

in which X, R3, R4 and m are as defined in claim 1, in a solvent. 5-10.(Cancelled)
 11. A process according to claim 4 wherein the solvent is analcohol, an ether, or a hydrocarbon.
 12. A process according to claim 11carried out in the presence of a base.
 13. A process according to claim11 carried out in the presence of a palladium-based or nickel-basedcatalyst.
 14. A process according to claim 12 carried out in thepresence of an alkali metal halide.
 15. A pharmaceutical compositionwhich comprises a compound according to claim 1 together with apharmaceutically acceptable excipient.
 16. A pharmaceutical compositionwhich comprises a compound according to claim 2 together with apharmaceutically acceptable excipient.
 17. A pharmaceutical compositionwhich comprises a compound according to claim 3 together with apharmaceutically acceptable excipient.
 18. A method for the treatment ofdisorders in which the enzyme poly (ADP-ribose) polymerase is involvedwhich comprises administering to a patient in need of such treatment atherapeutically effective amount of a compound having formula (I)

in which: R1 represents a hydrogen atom, a C1-C4 alkyl group, a halogenatom, a nitro group or a C1-C4 alkoxy group, R2 and R2′ represent,independently of each other, a hydrogen atom or a C1-C4 alkyl group, Xrepresents a nitrogen atom or a carbon atom, n is equal to 1 or 2, m isequal to 1 or 2, and, when X represents a nitrogen atom: R3 is notpresent or represents a C1-C4 alkyl group, and R4 represents a hydrogenatom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C3-C7heterocycloalkyl group optionally substituted with a C1-C4 alkyl groupor a group —COOR, in which R represents a C1-C6 alkyl group, a group—(CH₂)_(p)-heteroaryl, in which p may range from 0 to 4 and in which theheteroaryl group is chosen from pyridyl, aminopyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, imidazolyl and thienyl groups, the saidheteroaryl group optionally being substituted with a C1-C4 alkyl group,a heteroarylcarbonyl group, the heteroaryl group being chosen fromfuryl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and imidazolyl groups,a phenylcarbonyl group, the phenyl group optionally being substitutedwith a halogen atom, a (C1-C6)alkylcarbonyl group, a group—(CH₂)_(p)COOR in which p may range from 0 to 4 and in which Rrepresents a C1-C6 alkyl group, a phenylsulphonyl group optionallysubstituted on the phenyl nucleus with a halogen atom, a trifluoromethylgroup, a C1-C4 alkyl group, a nitro group or a C1-C4 alkoxy group, or a—(CH₂)_(p)-phenyl group, in which p may range from 0 to 4 and in whichthe phenyl group is optionally substituted with one to three groupschosen, independently of each other, from: a C1-C4 alkyl group, a nitrogroup, an amino group, a hydroxyl group, a halogen atom, atrifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenylgroup, a C1-C4 alkylamino group, a C1-C4 dialkylamino group, an —NHCHOgroup or a group —NHCOR′, in which R′ represents a C1-C4 alkoxy group ora C1-C4 alkyl group, this C1-C4 alkyl group optionally being substitutedwith a dimethylamino group, and, when X represents a carbon atom: R3represents a hydrogen atom, a group —NR5R6, a group —N(R5)₃ ⁺, a group—NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH₂ group, an —OH groupor a —CH₂OH group, R4 represents a hydrogen atom, a —(CH₂)_(p)-phenylgroup, in which p may range from 0 to 4 and in which the phenyl group isoptionally substituted with one to three groups chosen, independently ofeach other, from: a C1-C4 alkyl group, a nitro group, an amino group, ahalogen atom, a trifluoromethyl group or a C1-C4 alkoxy group, a—(CH₂)_(p)-heteroaryl group, in which p may range from 0 to 4 and inwhich the heteroaryl group is chosen from an imidazolyl group,optionally substituted with a C1-C4 alkyl group, a pyridyl group, anaminopyridyl group, a pyrimidinyl group, a pyrazinyl group or apyridazinyl group, or a group —(CH₂)_(t)NR7R8, in which t is equal to 0or 1, R5 and R6 represent, independently of each other, a hydrogen atomor a C1-C4 alkyl group, and R7 and R8 represent, independently of eachother, a C1-C4 alkyl or C1-C4 alkoxy group or together form a saturated5- to 7-membered ring optionally comprising an additional nitrogen atom,this ring optionally being substituted, on a carbon atom or on anitrogen atom, including the nitrogen atom to which the groups R7 and R8are attached, with a C1-C4 alkyl group or a group —COOR″, in which R″represents a phenyl or (C1-C4)alkylphenyl group, or a pharmaceuticallyacceptable acid addition salt thereof, with the proviso that when R4represents a group —NR7R8, R3 is other than —NR5R6, —NHCOR7, —NHCONH₂ or—OH, and when R1=R2=R2′=R3=H, X=C and n=m=1, R4 is other than4-imidazolyl or 5-methyl-4-imidazolyl.
 19. A method according to claim18 wherein: X is a nitrogen atom and R3 is not present, R1 represents ahydrogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, R2represents a hydrogen atom or a C1-C4 alkyl group, R2′ represents ahydrogen atom, n is equal to 1 or 2, m is equal to 1 or 2, and R4represents a hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkylgroup, a pyridyl, pyrimidinyl or pyrazinyl group, optionally substitutedwith a C1-C4 alkyl group, a heteroarylcarbonyl group, the heteroarylgroup being chosen from a furyl group and a pyridyl group, aphenylcarbonyl group, the phenyl group optionally being substituted witha halogen atom, a (C1-C6)alkylcarbonyl group, a group —(CH₂)_(p)COOR inwhich p can range from 0 to 4 and in which R represents a C1-C6 alkylgroup, a phenylsulphonyl group, a phenyl group substituted with one tothree groups chosen, independently of each other, from: a C1-C4 alkylgroup, a nitro group, an amino group, a hydroxyl group, a halogen atom,a trifluoromethyl group, a C1-C4 alkoxy group, a (C1-C4)alkoxyphenylgroup, a (C1-C4)- dialkylamino group, an —NHCHO group or a group—NHCOR′, in which R′ represents a C1-C4 alkoxy group or a C1-C4 alkylgroup, this C1-C4 alkyl group optionally being substituted with adimethylamino group, a —(CH₂)_(p)-phenyl group, in which p can rangefrom 0 to 4, a —(CH₂)_(p)-pyridyl group, in which p can range from 0 to4, a —(CH₂)_(p)-thienyl group, in which p can range from 0 to 4, or a(C3-C7)heterocycloalkyl group optionally substituted with a C1-C4 alkylgroup or a group —COOR, in which R represents a C1-C6 alkyl group, or Xis a carbon atom and R3 is a hydrogen atom, a group —NR5R6, a group—N(R5)₃ ⁺, a group —NHCOR7, a group —CONHR5, an —NHCONH₂ group, an —OHgroup or a —CH₂OH group, R1 represents a hydrogen atom, R2 and R2′represent, independently of each other, a hydrogen atom or a C1-C4 alkylgroup, n is equal to 1 or 2, m is equal to 1, R4 represents a hydrogenatom, a benzyl group, a phenyl group optionally substituted with one tothree groups chosen, independently of each other, from: a C1-C4 alkylgroup, a nitro group, an amino group, a halogen atom, a trifluoromethylgroup or a C1-C4 alkoxy group, a heteroaryl group chosen from animidazolyl group, optionally substituted with a C1-C4 alkyl group, or apyridyl group, or a group —NR7R8, R5 and R6 represent, independently ofeach other, a hydrogen atom or a C1-C4 alkyl group, and R7 and R8represent, independently of each other, a C1-C4 alkyl or C1-C4 alkoxygroup, or together form a saturated 5- to 7-membered ring optionallycomprising an additional nitrogen atom, this ring optionally beingsubstituted, on a carbon atom or a nitrogen atom, including the nitrogenatom to which the groups R7 and R8 are attached to form a quaternaryammonium, with a C1-C4 alkyl group or a group —COOR″, in which R″represents a phenyl or (C1-C4)alkylphenyl group.
 20. A method accordingto claim 19 wherein: X is a nitrogen atom and R3 is not present, R1represents a hydrogen atom, a methyl group or a methoxy group, R2represents a hydrogen atom or a methyl group, R2′ represents a hydrogenatom, n is equal to 1 or 2, m is equal to 1 or 2, and R4 represents ahydrogen atom, a C1-C4 alkyl group, a C6-C7 cycloalkyl group, a pyridyl,pyrimidinyl or pyrazinyl group, optionally substituted with a C1-C4alkyl group, a heteroarylcarbonyl group, the heteroaryl group beingchosen from a furyl group and a pyridyl group, a phenylcarbonyl group,the phenyl group optionally being substituted with a halogen atom, a(C3-C5)alkylcarbonyl group, a group —(CH₂)_(p)COOR in which p is equalto 0 or 1 and in which R represents a C1-C4 alkyl group, aphenylsulphonyl group, a phenyl group substituted with one to threegroups chosen, independently of each other, from: a methyl group, anitro group, an amino group, a hydroxyl group, a halogen atom, atrifluoromethyl group, a methoxy group, a (C1-C4)alkoxyphenyl group, adimethylamino group, an —NHCHO group or a group —NHCOR′, in which R′represents a C1-C4 alkoxy group or a C1-C4 alkyl group, this C1-C4 alkylgroup optionally being substituted with a dimethylamino group, a—(CH₂)_(p)-phenyl group, in which p is equal to 1, 2, 3 or 4, a—(CH₂)_(p)-pyridyl group, in which p can range from 1 to 3, a—(CH₂)_(p)-thienyl group, in which p is equal to 2, or a C6-C7heterocycloalkyl group optionally substituted with a methyl group or agroup —COOR, in which R represents a C1-C4 alkyl group, or X is a carbonatom R3 is a hydrogen atom, a group —NR5R6, an —N(CH₃)₃ ⁺ group, a group—NHCOR7, a group —CONHR5, an —NHCONH₂ group, an —OH group or a —CH₂OHgroup, R1 represents a hydrogen atom, R2 and R2′ represent,independently of each other, a hydrogen atom or a methyl group, n isequal to 1 or 2, m is equal to 1, R4 represents a hydrogen atom, abenzyl group, a phenyl group optionally substituted with one to threegroups chosen, independently of each other, from a halogen atom and atrifluoromethyl group, a heteroaryl group chosen from an imidazolylgroup, optionally substituted with a methyl group, or a pyridyl group,or a group —NR7R8, R5 and R6 represent, independently of each other, ahydrogen atom or a C1-C4 alkyl group, and R7 and R8 represent,independently of each other, a C1-C4 alkyl group or together form asaturated 5- to 7-membered ring optionally comprising an additionalnitrogen atom, this ring optionally being substituted, on a carbon atomor on a nitrogen atom, including the nitrogen atom to which the groupsR7 and R8 are attached to form a quaternary ammonium, with a methylgroup or a group —COOR″, in which R″ represents a (C1-C4)alkylphenylgroup.
 21. A method according to claim 18 wherein the disorders areselected from myocardial infarction, cardiac ischemia, cardiacinsufficiency, atherosclerosis, restenosis after PTCA or bypass,cerebral ischemia and cerebral infarction, caused by an ischemia, atrauma or a thromboembolic accident, neurodegenerative diseases such asParkinson's disease, Alzheimer's disease and Huntington's chorea, acuterenal insufficiency, in particular that of ischemic origin or appearingafter kidney transplant, heart transplant: treatment of graft rejectionand accelerated atherosclerosis of grafts, inflammatory pathologies,immunological disorders, rheumatoid diseases, diabetes and pancreatitis,septic shock, acute respiratory distress syndrome, tumours andmetastases, autoimmune diseases, AIDS, hepatitis, psoriasis, vasculitis,ulcerative colitis, multiple sclerosis or myasthenia.
 22. A methodaccording to claim 19 wherein the disorders are selected from myocardialinfarction, cardiac ischemia, cardiac insufficiency, atherosclerosis,restenosis after PTCA or bypass, cerebral ischemia and cerebralinfarction, caused by an ischemia, a trauma or a thromboembolicaccident, neurodegenerative diseases such as Parkinson's disease,Alzheimer's disease and Huntington's chorea, acute renal insufficiency,in particular that of ischemic origin or appearing after kidneytransplant, heart transplant: treatment of graft rejection andaccelerated atherosclerosis of grafts, inflammatory pathologies,immunological disorders, rheumatoid diseases, diabetes and pancreatitis,septic shock, acute respiratory distress syndrome, tumours andmetastases, autoimmune diseases, AIDS, hepatitis, psoriasis, vasculitis,ulcerative colitis, multiple sclerosis or myasthenia.
 23. A methodaccording to claim 20 wherein the disorders are selected from myocardialinfarction, cardiac ischemia, cardiac insufficiency, atherosclerosis,restenosis after PTCA or bypass, cerebral ischemia and cerebralinfarction, caused by an ischemia, a trauma or a throboembolic accident,neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease and Huntington's chorea, acute renal insufficiency, inparticular that of ischemic origin or appearing after kidney transplant,heart transplant: treatment of graft rejection and acceleratedatherosclerosis of grafts, inflammatory pathologies, immunologicaldisorders, rheumatoid diseases, diabetes and pancreatitis, septic shock,acute respiratory distress syndrome, tumours and metastases, autoimmunediseases, AIDS, hepatitis, psoriasis, vasculitis, ulcerative colitis,multiple sclerosis or myasthenia.
 24. A method for the treatment ofdisorders in which the enzyme poly(ADP-ribose) polymerase is involvedwhich comprises administering to a patient in need of such treatment atherapeutically effective amount of a compound of the formula

in which R4 is 4-imidazolyl or 5-methyl-4imidazolyl.